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CCK1 receptor is essential for normal meal patterning in mice fed high fat diet
Abstract
Cholecystokinin (CCK), released by lipid in the intestine, initiates satiety by acting at cholecystokinin type 1 receptors (CCK(1)Rs) located on vagal afferent nerve terminals located in the wall of the gastrointestinal tract. In the present study, we determined the role of the CCK(1)R in the short term effects of a high fat diet on daily food intake and meal patterns using mice in which the CCK(1)R gene is deleted. CCK(1)R(-/-) and CCK(1)R(+/+) mice were fed isocaloric high fat (HF) or low fat (LF) diets ad libitum for 18 h each day and meal size, meal frequency, intermeal interval, and meal duration were determined. Daily food intake was unaltered by diet in the CCK(1)R(-/-) compared to CCK(1)R(+/+) mice. However, meal size was larger in the CCK(1)R(-/-) mice compared to CCK(1)R(+/+) mice when fed a HF diet, with a concomitant decrease in meal frequency. Meal duration was increased in mice fed HF diet regardless of phenotype. In addition, CCK(1)R(-/-) mice fed a HF diet had a 75% decrease in the time to 1st meal compared to CCK(1)R(+/+) mice following a 6 h fast. These data suggest that lack of the CCK(1)R results in diminished satiation, causing altered meal patterns including larger, less frequent meals when fed a high fat diet. These results suggest that the CCK(1)R is involved in regulating caloric intake on a meal to meal basis, but that other factors are responsible for regulation of daily food intake.
... Studies from several laboratories have indicated that diet-induced obesity (DIO) compromises the excitability and responsiveness of peripheral vagal afferents (Covasa et al. 2000a,b;Donovan et al. 2007;Little et al. 2007;Paulino et al. 2009;Daly et al. 2011;de Lartigue et al. 2011) as well as central vagal efferents (Browning et al. 2013b). Roux-en-Y gastric bypass-induced weight loss reversed some, but not all, of the DIO-induced alterations of vagal efferents, suggesting that a high fat diet (HFD) may alter neurones independently of obesity (Browning et al. 2013b). ...
... The behaviour and activity of vagal afferents is known to be remarkably labile; pathophysiological conditions such as insult or injury modulate afferent activity (Moore et al. 2000;Bielefeldt et al. 2002a,b;Gebhart et al. 2002;Kollarik & Undem, 2002, 2004Myers et al. 2002;Dang et al. 2004;Tolstykh et al. 2004;Hermes et al. 2008). Similarly, the behaviour of vagal afferents is impacted adversely by diet-induced obesity (Covasa et al. 2000a,b;Donovan et al. 2007;Paulino et al. 2009;Daly et al. 2011;de Lartigue et al. 2011;Kentish et al. 2012). The activity and behaviour of vagal afferents appears surprisingly dynamic, however, and respond to ongoing physiological demands (Burdyga et al. 2006;Dockray, 2009) even perhaps on a minute-to-minute basis (Babic et al. 2012). ...
... Studies from several laboratories have demonstrated that the excitability and responsiveness of vagal afferent neurones and peripheral terminals is decreased following the development of DIO (Covasa et al. 2000a,b;Donovan et al. 2007;Paulino et al. 2009;Daly et al. 2011;de Lartigue et al. 2011;Kentish et al. 2012). Results from the present study would suggest that, even in the J Physiol 593.1 absence of obesity, exposure to perinatal HFD also decreases the release of glutamate from central vagal afferents and attenuates the tonic activation of presynaptic group II mGluRs. ...
Key points
Obesity is recognized as being multifactorial in origin, involving both genetic and environmental factors. The perinatal period is known to be critically important in the development of neural circuits responsible for energy homeostasis and the integration of autonomic reflexes.
Diet‐induced obesity alters the biophysical, pharmacological and morphological properties of vagal neurocircuits regulating upper gastrointestinal tract functions, including satiety. Less information is available, however, regarding the effects of a high fat diet (HFD) itself on the properties of vagal neurocircuits.
The present study was designed to test the hypothesis that exposure to a HFD during the perinatal period alters the electrophysiological, pharmacological and morphological properties of vagal efferent motoneurones innervating the stomach.
Our data indicate that perinatal HFD decreases the excitability of gastric‐projecting dorsal motor nucleus neurones and dysregulates neurotransmitter release from synaptic inputs and that these alterations occur prior to the development of obesity. These findings represent the first direct evidence that exposure to a HFD modulates the processing of central vagal neurocircuits even in the absence of obesity.
Abstract
The perinatal period is critically important to the development of autonomic neural circuits responsible for energy homeostasis. Vagal neurocircuits are vital to the regulation of upper gastrointestinal functions, including satiety. Diet‐induced obesity modulates the excitability and responsiveness of both peripheral vagal afferents and central vagal efferents but less information is available regarding the effects of diet per se on vagal neurocircuit functions. The aims of this study were to investigate whether perinatal exposure to a high fat diet (HFD) dysregulated dorsal motor nucleus of the vagus (DMV) neurones, prior to the development of obesity. Whole cell patch clamp recordings were made from gastric‐projecting DMV neurones in thin brainstem slices from rats that were exposed to either a control diet or HFD from pregnancy day 13. Our data demonstrate that following perinatal HFD: (i) DMV neurones had decreased excitability and input resistance with a reduced ability to fire action potentials; (ii) the proportion of DMV neurones excited by cholecystokinin (CCK) was unaltered but the proportion of neurones in which CCK increased excitatory glutamatergic synaptic inputs was reduced; (iii) the tonic activation of presynaptic group II metabotropic glutamate receptors on inhibitory nerve terminals was attenuated, allowing modulation of GABAergic synaptic transmission; and (iv) the size and dendritic arborization of gastric‐projecting DMV neurones was increased. These results suggest that perinatal HFD exposure compromises the excitability and responsiveness of gastric‐projecting DMV neurones, even in the absence of obesity, suggesting that attenuation of vago‐vagal reflex signalling may precede the development of obesity.
... OLETF rats consume meals that are about twice the normal size and while these animals decrease their meal numbers, the response is insufficient to normalize their intake resulting in overall hyperphagia, obesity [118] and, with age, hyperglycemia [119]. CCK1R knock out mice also consume larger meals but successfully compensate for their larger meals, have a normal body size [120], and remain normoglycemic [121]. These species differences in phenotype resulting from lack of CCK1R highlight a problem with the use of genetic models that may be related to differences in receptor distribution, compensation mechanisms, or, in the case of the OLETF rats, additional mutations that promote a specific phenotype. ...
... General genetic loss of CCK1R leads to obesity in rats [118] and altered feeding patterns in mice [120]. Recent work using a precise technique to specifically target and eliminate CCK receptor expressing VAN with saporin conjugated to CCK (CCK-SAP) verifies the need for the vagal CCK pathway in maintenance of normal feeding patterns and response to specific nutrients [259]. ...
In 1973, Gibbs, Young, and Smith showed that exogenous cholecystokinin (CCK) administration reduces food intake in rats. This initial report has led to thousands of studies investigating the physiological role of CCK in regulating feeding behavior. CCK is released from enteroendocrine I cells present along the gastrointestinal (GI) tract. CCK binding to its receptor CCK1R leads to vagal afferent activation providing post-ingestive feedback to the hindbrain. Vagal afferent neurons’ (VAN) sensitivity to CCK is modulated by energy status while CCK signaling regulates gene expression of other feeding related signals and receptors expressed by VAN. In addition to its satiation effects, CCK acts all along the GI tract to optimize digestion and nutrient absorption. Diet-induced obesity (DIO) is characterized by reduced sensitivity to CCK and every part of the CCK system is negatively affected by chronic intake of energy-dense foods. EEC have recently been shown to adapt to diet, CCK1R is affected by dietary fats consumption, and the VAN phenotypic flexibility is lost in DIO. Altered endocannabinoid tone, changes in gut microbiota composition, and chronic inflammation are currently being explored as potential mechanisms for diet driven loss in CCK signaling. This review discusses our current understanding of how CCK controls food intake in conditions of leanness and how control is lost in chronic energy excess and obesity, potentially perpetuating excessive intake.
... This study though is the Vol. 16 No. 1 2017 28 first to clarify immunohistochemically the type and distribution of neuroenteroendocrine cells in small intestine of sheep. ...
... Most of the CCKimmunoreactive (IR) cells were flask shaped with apices pointing towards the lumen of the gut. This expression of the CCK has been found in agreement with (23) in camel (28) in sheep, the CCK hormone in duodenum and subsequently was decreased in jejunum and ileum, this finding was supported by (23,29,30) in mammals and camel. Cholecystokinin (CCK-8) was released by lipid in the intestine to initiates satiety by acting at cholecystokinin type 1 receptors (CCK1Rs) located on vagal afferent nerve terminals located in the wall of the gastrointestinal tract (27), CCK in the upper small intestine may be associated to the role of these hormones in the stimulation of intestinal and gallbladder smooth muscle and pancreatic secretion (31, 32,33).The cells are located to the crypts and the villi, they are more numerous in the crypts compared to the villi, the shape of the cells varies according to the segment of the gut, the neurotransmitters and neuropeptide-IR cells were generally spherical or spindle shaped (open type cells), while cells that were rounded in shape (closed-type cells) were occasionally seen. ...
AL-Qadisiyah Journal of Vet. Med. Sci. Vol. 16 No. 1 2017 23 Detection of cholecystokinin and glucagon like peptide in small intestine of Awassi sheep Huda Shadhan Awadha Eman Fasial Abdall Hassan** Coll. of Vet. Med. / Univ. of Al-Qadisiyah **E-mail: Eman.Fasial@qu.edu.iq (Received 18/4/2017, Accepted 2/5/2017) Abstract The enter endocrine cells in small intestine of sheep secreting some hormones that play key roles in regulation of certain important organs. The endocrine cells of GIT are generally divided into two types, the open and close type.The aim of this study was unveil the relative frequency and regional distribution of enteroendocrine cells in some portions of small intestine of the Awassi sheep, detecting by using immunohistochemistry techniques. Specimens of small intestine from ten of both sexes with different ages of sheep Ovis aries were used. The Immunohistochemistry technique formed using two types of hormones cholecystokinin (CCK-8) and glucagon like peptide (GLP-1). Result of immune detection findings demonstrated that in part of small intestine (duodenum, jejunum and ileum) there is clearly expression of the CCK-8 and GLP-1 subset of cells along the villus and crypts. The cells are contained gut hormones appeared to be either triangular or flask-like in shape. I-cell which contain CCK-8 increase proximally of small intestine and decrease caudally, while L-cell which contain GLP-1 decrease proximally but increase caudally of small intestine. Key words: Endocrine cells, intestinal tract, immunohistochemistry, hormones
(8) (PDF) Detection of cholecytokinin(CCK-8)and glucagon like peptide (GLP-1) in small intestine of Awassi sheep. Available from: https://www.researchgate.net/publication/320676821_Detection_of_cholecytokininCCK-8and_glucagon_like_peptide_GLP-1_in_small_intestine_of_Awassi_sheep [accessed Apr 26 2021].
... CAVI amount was not differing between the genotypes at 6 or 18 weeks (Fig. 3A and B, p = 0.676 and 0.647) and underlined unaltered appetite consistent with unchanged food intake. For trypsin, it has been shown that it reduces the secretion of the hormone cholecystokinin, which regulates meal patterns in mice (CCK, [37,38]). The fecal trypsin amount was diminished in young 5xFAD animals to about 40-50% of control ( Fig. 3A and B, p = 0.010 and 0.045). ...
... Interestingly, trypsin also negatively influences the amount of cholecystokinin which initiates satiety by acting on receptors located on vagal afferent nerve terminals in the gastrointestinal tract wall. Mice with deleted CCK1 receptor for example displayed altered meal patterns when fed a high fat diet, although daily food was not affected [38]. An imbalanced CCK-driven feeding behavior, besides the reduced proteolytic break-down of nutritional proteins, could be involved in the observed early reduction in body weight of the 5xFAD mice. ...
The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut - the enteric nervous system, or even derive from there. By using a murine Alzheimer's disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer's disease in humans, directly interferes with gut function as shown here for the disease model mice.
... Several studies have demonstrated that the behaviour, activity and responsiveness of vagal afferents are altered by diet and obesity. The ability of CCK to activate vagal afferents is attenuated in rodents with diet-induced obesity (DIO; Covasa et al. 2000a,b;Donovan et al. 2007) and obese humans (Little et al. 2007), while a high-fat diet (HFD) alters receptor profiles on vagal afferent neurones (Paulino et al. 2009). Very little attention has been focused, however, on the effects of either diet or obesity on the membrane properties and responsiveness of central neurones, although electrophysiological studies have demonstrated that hypothalamic neurones in obese Zucker rats have a decreased responsiveness to neuropeptide Y (Pronchuk & Colmers, 2004) and leptin (Spanswick et al. 1997). ...
... Rather, vagal neurocircuits appear remarkably plastic and, in addition to modulating their responses following insult or injury (Moore et al. 2000;Bielefeldt et al. 2002a,b;Kollarik & Undem, 2002;Myers et al. 2002;Mei et al. 2003;Dang et al. 2004;Tolstykh et al. 2004;Kollarik et al. 2007;Hermes et al. 2008;Zhang et al. 2008), they appear capable of modulating their responses according to ongoing physiological demands (Burdyga et al. 2006;Dockray, 2009;, perhaps even on a minute-to-minute basis (Babic et al. 2012). It is well established that HFD, or HFD-induced obesity, alters the activity, sensitivity and responsiveness of vagal afferent nerves in rodents (Daly et al. 2011;de Lartigue et al. 2011;Kentish et al. 2012) and decreases the afferent-induced activation of NTS neurones within the brainstem (Covasa et al. 2000a,b;Donovan et al. 2007;Little et al. 2007;Nefti et al. 2009). Few studies have investigated the effects of diet or obesity on vagal afferent neurones themselves, although Daly et al. (2011) showed a decrease in the excitability of mouse vagal afferent neurones as a consequence of DIO. ...
Key points
Diet‐induced obesity (DIO) is known to alter the biophysical and pharmacological properties of gastrointestinal vagal afferent (sensory) neurones and fibres.
Little information is available, however, regarding the effects of DIO on the properties of central neurones involved in vagally mediated visceral reflexes.
The present study was designed to test the hypothesis that DIO alters the biophysical, pharmacological and morphological properties of vagal efferent motoneurones and that these alterations would be reversed following weight loss induced by Roux‐en‐Y gastric bypass.
Our data indicate that DIO decreases the excitability of vagal efferent neurones and attenuates their responses to the satiety neurohormones cholecystokinin and glucagon‐like peptide 1. These DIO‐induced changes were reversed following Roux‐en‐Y gastric bypass, suggesting that the alterations were due to obesity, rather than diet. These findings represent the first direct evidence that Roux‐en‐Y gastric bypass improves the functioning and responsiveness of central vagal neurocircuits by reversing some of the effects induced by DIO.
Abstract Diet‐induced obesity (DIO) has been shown to alter the biophysical properties and pharmacological responsiveness of vagal afferent neurones and fibres, although the effects of DIO on central vagal neurones or vagal efferent functions have never been investigated. The aims of this study were to investigate whether high‐fat diet‐induced DIO also affects the properties of vagal efferent motoneurones, and to investigate whether these effects were reversed following weight loss induced by Roux‐en‐Y gastric bypass (RYGB) surgery. Whole‐cell patch‐clamp recordings were made from rat dorsal motor nucleus of the vagus (DMV) neurones in thin brainstem slices. The DMV neurones from rats exposed to high‐fat diet for 12–14 weeks were less excitable, with a decreased membrane input resistance and decreased ability to fire action potentials in response to direct current pulse injection. The DMV neurones were also less responsive to superfusion with the satiety neuropeptides cholecystokinin and glucagon‐like peptide 1. Roux‐en‐Y gastric bypass reversed all of these DIO‐induced effects. Diet‐induced obesity also affected the morphological properties of DMV neurones, increasing their size and dendritic arborization; RYGB did not reverse these morphological alterations. Remarkably, independent of diet, RYGB also reversed age‐related changes of membrane properties and occurrence of charybdotoxin‐sensitive (BK) calcium‐dependent potassium current. These results demonstrate that DIO also affects the properties of central autonomic neurones by decreasing the membrane excitability and pharmacological responsiveness of central vagal motoneurones and that these changes were reversed following RYGB. In contrast, DIO‐induced changes in morphological properties of DMV neurones were not reversed following gastric bypass surgery, suggesting that they may be due to diet, rather than obesity. These findings represent the first direct evidence for the plausible effect of RYGB to improve vagal neuronal health in the brain by reversing some effects of chronic high‐fat diet as well as ageing. Vagovagal neurocircuits appear to remain open to modulation and adaptation throughout life, and understanding of these mechanisms may help in development of novel interventions to alleviate environmental (e.g. dietary) ailments and also alter neuronal ageing.
... CCK plays an important role in determining the size of each meal (30). CCK A receptor-deficient mice (31) and PrRP-deficient animals (18) show increased meal size. ...
... Meal size is regulated by satiety signals that terminate each meal. One important satiety signal is CCK (30), which is released from the gut after each meal and acts on CCK A receptors on afferent fibres of the gastric vagus nerve projecting to the medulla oblongata. CCK activates PrRP neurones in the medulla oblongata (38) and oxytocin neurones in the hypothalamus (12). ...
Food intake activates neurones expressing prolactin releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. Here, we investigated whether activation of oxytocin neurones following food intake is mediated by PrRP. We first examined expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated release of oxytocin and vasopressin. In mice, re-feeding increased expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or intraperitoneal administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor-deficient mice showed increased meal size, as reported in PrRP-deficient mice and in CCK(A) receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, activation of oxytocin neurones in response to food intake, and that the CCK-PrRP-oxytocin pathway plays an important role in the control of termination of each meal. © 2013 British Society for Neuroendocrinology.
... In addition, CCK-8S injected intraperitoneally reduces food intake in CCK 2 receptor but not in CCK 1 receptor knockout mice [140]. CCK 1 null mice have a markedly altered feeding pattern comprising of longer and bigger meals compared to their wild type littermates [141]. However, meal frequency was reduced resulting in a similar cumulative food intake [141]. ...
... CCK 1 null mice have a markedly altered feeding pattern comprising of longer and bigger meals compared to their wild type littermates [141]. However, meal frequency was reduced resulting in a similar cumulative food intake [141]. With regard to CCK knockout mice, they did not present alterations in overall food intake but gained significantly less body weight compared to their wild type littermates due to impaired absorption of fat and increased energy expenditure reflecting preferential use of carbohydrates [142]. ...
Several peptides are produced and released from endocrine cells scattered within the gastric oxyntic and the small intestinal mucosa. These peptide hormones are crucially involved in the regulation of gastrointestinal functions and food intake by conveying their information to central regulatory sites located in the brainstem as well as in the forebrain, such as hypothalamic nuclei. So far, ghrelin is the only known hormone that is peripherally produced in gastric X/A-like cells and centrally acting to stimulate food intake, whereas the suppression of feeding seems to be much more redundantly controlled by a number of gut peptides. Cholecystokinin produced in the duodenum is a well established anorexigenic hormone that interacts with ghrelin to modulate food intake indicating a regulatory network located at the first site of contact with nutrients in the stomach and upper small intestine. In addition, a number of peptides including leptin, urocortin 2, amylin and glucagon-like peptide 1 interact synergistically with CCK to potentiate its satiety signaling effect. New developments have led to the identification of additional peptides in X/A-like cells either derived from the pro-ghrelin gene by alternative splicing and posttranslational processing (obestatin) or a distinct gene (nucleobindin2/nesfatin-1) which have been investigated for their influence on food intake.
... These rats are obese and hyperphagic [32]. Mice lacking CCK receptors have increased meal size, but they compensate for this by decreasing meal frequency such that long-term food intake, and consequently body weight, is similar between control and knockout animals [33]. ...
Despite decades of obesity research and various public health initiatives, obesity remains a major public health concern. Our most drastic but most effective treatment of obesity is bariatric surgery with weight loss and improvements in co-morbidities, including resolution of type 2 diabetes (T2D). However, the mechanisms by which surgery elicits metabolic benefits are still not well understood. One proposed mechanism is through signals generated by the intestine (nutrients, neuronal, and/or endocrine) that communicate nutrient status to the brain. In this review, we discuss the contributions of gut-brain communication to the physiological regulation of body weight and its impact on the success of bariatric surgery. Advancing our understanding of the mechanisms that drive bariatric surgery-induced metabolic benefits will ultimately lead to the identification of novel, less invasive strategies to treat obesity.
... The role of the vagus nerve in eating patterns, now known to be essential for communication between the gut and the brain, was demonstrated in part via the impairment of meal patterns after vagotomy [26]. Hormones that are released in the gut or the brain as food is consumed have been shown to enhance the satiation of food by reducing the amount consumed in each meal [27][28][29][30][31]. Meal pattern analysis continues to be a useful tool when coupled with molecular methodologies such as measures and manipulations of specific hormones and neuronal subpopulations. ...
The measurement of the size and timing of meals provides critical insight into the processes underlying food intake. While most work has been conducted with a single food or fluid, the availability of food choices can also influence eating and interact with these processes. The 5-Item Food Choice Monitor (FCM), a device that continuously measures eating and drinking behaviors of rats provided up to 5 foods and 2 fluids simultaneously, was designed to allow study of food choices simultaneously with meal patterns. To validate this device, adult male and female (n=8 each) Sprague-Dawley rats were housed in the FCM. Food and fluid intake were measured continuously (22-h/day) while rats were presented water and powdered chow. Then then a cafeteria diet of 5 foods varying in macronutrient content, texture, and flavors were offered along with water. Lastly, the 5 foods were offered along with 0.3 M sucrose and water. Analyses were conducted to find optimal criteria for parceling ingestive behavior into meals, then meal patterns were quantified. Total intake, as assessed by FCM software, was in good concordance with that measured by an independent scale. A minimum meal size of 1 kcal and a meal termination criterion of 15-min accounted for >90% of total intake and produced meal dynamics that were in register with the literature. Use of the cafeteria diet allowed comparisons between meal patterns with a single food versus a multi-food diet, as well as analyses of macronutrient-related food choices across subsets of meals. The FCM proved to accurately measure food intake over a 22-h period and was able to detect differences and similarities in the meal patterns of rats as a function of sex and food choice availability. Combined with any number of experimental manipulations, the FCM holds great promise in the investigation of the physiological and neural controls of ingestive behavior in a dietary environment that allows food choices, more closely emulating human eating conditions.
... The increased expression is consistent with a previous study (Paulino et al. 2009) which demonstrated that the expression of CB1, GHSR and FAAH are increased in the whole nodose ganglia of diet-induced obese rats. It is plausible that the increased expression and interaction of these orexigenic factors may contribute to the increased meal sizes observed in obesity (Donovan et al. 2007;Paulino et al. 2008). However, this is highly speculative and requires further clarification. ...
Significance Statement
Gastric vagal afferent responses to tension are dampened in high fat diet‐induced obesity.
Endocannabinoids are known to dose‐dependently inhibit and excite gastric vagal afferents but their effect on gastric vagal afferents in diet‐induced obesity are unknown.
In individual gastric vagal afferent neurons of diet‐induced obese mice the co‐expression of components of the endocannabinoid system, including CB1, GHSR, TRPV1 and FAAH, was increased compared with lean mice.
In high fat diet‐induced obese mice, methanandamide only inhibited gastric vagal afferent responses to tension, possibly due to the observed change in the balance of receptors, hormones and breakdown enzymes in this system.
Collectively, these data suggest that endocannabinoid signalling, by gastric vagal afferents, is altered in diet‐induced obesity which may impact satiety and gastrointestinal function.
Abstract
Gastric vagal afferents (GVAs) play a role in appetite regulation. The endocannabinoid anandamide (AEA) dose‐dependently inhibits and excites tension‐sensitive GVAs. However, it is also known that high fat diet (HFD) feeding alters GVA responses to stretch. The aim of this study was to determine the role of AEA in GVA signalling in lean and HFD‐induced obese mice.
Male C57BL/6 mice were fed (12 weeks) a standard laboratory diet (SLD) or HFD. Protein and mRNA expression of components of the cannabinoid system was determined in individual GVA cell bodies and the gastric mucosa. An in vitro GVA preparation was used to assess the effect of methanandamide (mAEA) on tension‐sensitive GVAs and the second messenger pathways involved.
In individual GVA cell bodies, cannabinoid 1 (CB1) and ghrelin (GHSR) receptor mRNA was higher in HFD mice than SLD mice. Conversely, gastric mucosal AEA and ghrelin protein levels were lower in HFD mice than SLD mice. In SLD mice, mAEA exerted dose‐dependent inhibitory and excitatory effects on tension‐sensitive GVAs. Only an inhibitory effect of mAEA was observed in HFD mice. The excitatory effect of mAEA was dependent on CB1, transient receptor potential vanilloid 1 (TRPV1) and the protein kinase C. Conversely, the inhibitory effect was dependent on CB1, growth hormone secretagogue receptor, TRPV1 and the protein kinase A. Endocannabinoids, acting through CB1 and TRPV1, have a pivotal role in modulating GVA satiety signals depending on the second messenger pathway utilised. In HFD mice only an inhibitory effect was observed. These changes may contribute to the development and/or maintenance of obesity.
... Current research is investigating nerve sub-types and their roles in proper gut function. Cholecystokinin receptor (CCKR), a known afferent nerve receptor in the gut [133,134], was found to increase expression in the nodose ganglia (NG) of the vagus in response to obesity in high-fat diet fed diet-induced obesity prone (DIO-P) rats [135]. Recently, a method of selective ablation of afferent nerves (deafferentation) was developed, using a ribosomal inactivating protein, saporin (SAP), and CCK together as a conjugate. ...
Brown and white adipose tissues are essential for maintenance of proper energy balance and metabolic health. In order to function efficiently, these tissues require both endocrine and neural communication with the brain. Brown adipose tissue (BAT), as well as the inducible brown adipocytes that appear in white adipose tissue (WAT) after simulation, are thermogenic and energy expending. This uncoupling protein 1 (UCP1)-mediated process requires input from sympathetic nerves releasing norepinephrine. In addition to sympathetic noradrenergic signaling, adipose tissue contains sensory nerves that may be important for relaying fuel status to the brain. Chemical and surgical denervation studies of both WAT and BAT have clearly demonstrated the role of peripheral nerves in browning, thermogenesis, lipolysis, and adipogenesis. However, much is still unknown about which subtypes of nerves are present in BAT versus WAT, what nerve products are released from adipose nerves and how they act to mediate metabolic homeostasis, as well as which cell types in adipose are receiving synaptic input. Recent advances in whole-depot imaging and quantification of adipose nerve fibers, as well as other new research findings, have reinvigorated this field of research. This review summarizes the history of research into adipose innervation and brain–adipose communication, and also covers landmark and recent research on this topic to outline what we currently know and do not know about adipose tissue nerve supply and communication with the brain.
... Moreover, at higher systemic concentrations, e.g. as a result of exogenous GLP-1 administration, or supraphysiological postoperative levels, gut-brain communication can occur via vagally independent pathways to blunt food intake at meal time [116]. Other important hormones that have been shown to affect food intake and may contribute to the postprandial satiety response after upper GI surgery are depicted in table 1, including OXM [117,118], CCK [66,[119][120][121][122][123][124][125][126][127] and PP [128][129][130][131]. ...
Recent advances in the surgical and multimodality management of oesophageal cancer have led to improved survival for patients treated with curative intent. Survivors may struggle to adapt to the profound nutritional impact of oesophageal cancer surgery, and addressing dietary and related functional, and quality of life issues is an area of increased research focus. Mechanistic insight to explain significant weight loss has parallels in bariatric surgery. In particular, the gut–brain axis plays a pivotal role in energy balance and unintentional weight loss by influencing subconscious neural pathways, and key signalling pathways may be significantly altered in the context of major upper gastrointestinal surgery. In this review, we explore the core components comprising this gut–brain interplay, and outline the potential mechanisms underpinning the postoperative adaptations observed. We also discuss how this mechanism may affect weight and quality of life after oesophageal cancer resection. Only once the pathophysiological processes are understood are we likely to develop effective and sustainable therapeutic solutions.
... Furthermore, although mice lacking functional CCK-1 recep-445 tors demonstrated increased intake in acute feeding studies, and failed to respond to peripherally administered CCK, CCK-1r knock-out mice demonstrated similar long-term body weight to wild-type mice [132]. Additional data indicate that this may be due to compensatory increases in meal frequency 450 [133]. Overall, these data suggest that CCK, although a candidate post prandial satiety factor, may not be required for normal body weight maintenance. ...
Introduction: With the increasing prevalence of obesity and its associated comorbidities, strides to improve treatment strategies have enhanced our understanding of the function of the gut in the regulation of food intake. The most successful intervention for obesity to date, bariatric surgery effectively manipulates enteroendocrine physiology to enhance satiety and reduce hunger.
Areas covered: In the present article, we provide a detailed overview of the physiology of enteroendocrine control of food intake, and discuss its pathophysiologic correlates and therapeutic implications in both obesity and gastrointestinal disease.
Expert Commentary: Ongoing research in the field of nutrient sensing by L-cells, as well as understanding the role of the microbiome and bile acid signaling may facilitate the development of novel strategies to combat the rising population health threat associated with obesity. Further refinement of post-prandial satiety gut hormone based therapies, including the development of chimeric peptides exploiting the pleiotropic nature of the gut hormone response, and identification of novel methods of delivery may hold the key to optimization of therapeutic modulation of gut hormone physiology in obesity.
... Indeed, plasticity in the synapses between VAF and NTS neurons, which is crucial in maintaining efficient satiety signaling [39], after high-caloric intake alters the properties and the reactivity of the neurons of the brainstem nuclei [65][66][67]. ...
The current treatment for obesity-related type 2 diabetes is not able to achieve sufficient metabolic control. New remission prospects have been offered through bariatric surgery and other interventional therapies. The aim of the study is to illustrate the mechanism by which such therapies affect the autonomic system, in particular the afferent vagal activity. The first and most important terminal of this activity is the brainstem vagal nucleus tractus solitarius. Its function, on which the vagal efferent inputs that control the splanchnic organs depend, is conditioned by the level of synaptic transmission within it. In conclusion, on the basis of such a view, a selective pharmacological modulation of such transmission as the target for future medical treatment of obesity and related type 2 diabetes is proposed.
... Although, the regulation of food intake and energy homeostasis is generally considered to involve the integration of "higher" CNS centers with autonomic nuclei, the role of vago-vagal neurocircuits in the regulation of early satiety signaling has been the subject of renewed attention by several laboratory groups (Page et al., 2012;Dockray, 2013;de Lartigue, 2014;. Diet-induced obesity is known to compromise the excitability and responsiveness of GI vagal afferent fibers (Covasa et al., 2000a,b;Swartz et al., 2010;Kentish et al., 2012) and neurons (Donovan et al., 2007;Paulino et al., 2009;Daly et al., 2011;de Lartigue et al., 2011). The mechanism responsible for this attenuated excitability has not been elucidated fully although studies in both obese mice and rats demonstrating a decreased membrane input resistance and increased membrane capacitance are suggestive of an increase in resting background potassium conductance(s) (Daly et al., 2011;Browning et al., 2013b). ...
Vagal neurocircuits are vitally important in the co-ordination and modulation of GI reflexes and homeostatic functions. 5-hydroxytryptamine (5-HT; serotonin) is critically important in the regulation of several of these autonomic gastrointestinal (GI) functions including motility, secretion and visceral sensitivity. While several 5-HT receptors are involved in these physiological responses, the ligand-gated 5-HT3 receptor appears intimately involved in gut-brain signaling, particularly via the afferent (sensory) vagus nerve. 5-HT is released from enterochromaffin cells in response to mechanical or chemical stimulation of the GI tract which leads to activation of 5-HT3 receptors on the terminals of vagal afferents. 5-HT3 receptors are also present on the soma of vagal afferent neurons, including GI vagal afferent neurons, where they can be activated by circulating 5-HT. The central terminals of vagal afferents also exhibit 5-HT3 receptors that function to increase glutamatergic synaptic transmission to second order neurons of the nucleus tractus solitarius within the brainstem. While activation of central brainstem 5-HT3 receptors modulates visceral functions, it is still unclear whether central vagal neurons, i.e., nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMV) neurons themselves also display functional 5-HT3 receptors. Thus, activation of 5-HT3 receptors may modulate the excitability and activity of gastrointestinal vagal afferents at multiple sites and may be involved in several physiological and pathophysiological conditions, including distention- and chemical-evoked vagal reflexes, nausea, and vomiting, as well as visceral hypersensitivity.
... Studies from many laboratories have demonstrated that the excitability and responsiveness of GI vagal afferent neurones and fibres is modulated by exposure to a high fat diet (HFD) or by diet-induced obesity (Donovan et al. 2007;Daly et al. 2011;de Lartigue et al. 2011;Kentish et al. 2012). Few studies, however, have investigated either the effects of a high fat diet on the responsiveness of vagal afferents before obesity develops or whether the attenuated responsiveness of vagal afferents occurs in response to obesity. ...
Key points
Glucose regulates the density and function of 5‐HT 3 receptors on gastric vagal afferent neurones.
Diet‐induced obesity compromises the excitability and responsiveness of vagal afferents.
In this study, we assessed whether exposure to a high fat diet (HFD) compromises the glucose‐dependent modulation of 5‐HT responses in gastric vagal afferents prior to the development of obesity.
We show that HFD does not alter the response of gastric vagal afferent nerves and neurones to 5‐HT but attenuates the ability of glucose to amplify 5‐HT 3 ‐induced responses.
These results suggest that glucose‐dependent vagal afferent signalling is compromised by relatively short periods of exposure to HFD well in advance of the development of obesity or glycaemic dysregulation.
Abstract
Glucose regulates the density and function of 5‐HT 3 receptors on gastric vagal afferent neurones. Since diet‐induced obesity attenuates the responsiveness of gastric vagal afferents to several neurohormones, the aim of the present study was to determine whether high fat diet (HFD) compromises the glucose‐dependent modulation of 5‐HT responses in gastric vagal afferents prior to the development of obesity. Rats were fed control or HFD (14% or 60% kilocalories from fat, respectively) for up to 8 weeks. Neurophysiological recordings assessed the ability of 5‐HT to increase anterior gastric vagal afferent nerve (VAN) activity in vivo before and after acute hyperglycaemia, while electrophysiological recordings from gastric‐projecting nodose neurones assessed the ability of glucose to modulate the 5‐HT response in vitro . Immunocytochemical studies determined alterations in the neuronal distribution of 5‐HT 3 receptors. 5‐HT and cholecystokinin (CCK) induced dose‐dependent increases in VAN activity in all rats; HFD attenuated the response to CCK, but not 5‐HT. The 5‐HT‐induced response was amplified by acute hyperglycaemia in control, but not HFD, rats. Similarly, although 5‐HT induced an inward current in both control and HFD gastric nodose neurones in vitro , the 5‐HT response and receptor distribution was amplified by acute hyperglycaemia only in control rats. These data suggest that, while HFD does not affect the response of gastric‐projecting vagal afferents to 5‐HT, it attenuates the ability of glucose to amplify 5‐HT effects. This suggests that glucose‐dependent vagal afferent signalling is compromised by short periods of exposure to HFD well in advance of obesity or glycaemic dysregulation.
... Alternatively, HFD impaired fatty acid uptake by inguinal fat in CCK-KO mice while CCK-KO mice on LFD have normal uptake of fatty acids. When fed a HFD, CCK1R-KO mice have increased meal size and reduced meal frequency, which results in comparable level of total food intake, weight gain and fat mass as WT mice [84,97]. The CCK-2R but not the CCK-1R has been implicated in the regulation of fat mass [77,81,84]. ...
Cholecystokinin (CCK) is released in response to lipid feeding and regulates pancreatic digestive enzymes vital to the absorption of nutrients.Our previous reports demonstrated that cholecystokinin knockout (CCK-KO) mice fed a 10weeks of HFD had reduced body fat mass, but comparable glucose uptake by white adipose tissues and skeletal muscles.We hypothesized that CCK is involved in energy homeostasis and lipid transport from small intestine to tissues in response to acute treatment with dietary lipids.CCK-KO mice with comparable fat absorption had increased energy expenditure and were resistant to HFD-induced obesity.Using intraduodenal infusion of butter fat and intravenous infusion using Liposyn III, we determined the mechanism of lipid transport from small intestine to deposition in lymph and adipocytes in CCK-KO mice.CCK-KO mice had delayed secretion of Apo B48-chylomicrons, lipid transport to the lymphatic system, and triglyceride (TG)-derived fatty acid uptake by epididymal fat in response to acute treatment of introdudenal lipids.In contrast, CCK-KO mice had comparable TG clearance and lipid uptake by white adipocytes in response to TG in chylomicron-like emulsion.Thus, we concluded that CCK is important for lipid transport and energy expenditure to control body weight in response to dietary lipid feeding.
Copyright © 2015. Published by Elsevier Inc.
... Several studies have shown that the behavior, activity and responsiveness of vagal afferent neurons and fibers are altered by diet and obesity. The ability of GI neurohormones such as GLP-1 and CCK to activate vagal afferents and decrease feeding is attenuated in diet-induced obese animal models and humans (112,113,126,142,145,299,536) and exposure to a high fat diet alters the profile of neurotransmitter/ neuromodulator receptors on vagal afferent neurons (131,369). While little attention has been paid to the effects of diet or obesity on the properties of central neurons, a recent study demonstrated that the responsiveness of vagal motoneurons was also decreased in diet-induced obese rodents (71). ...
Although the gastrointestinal (GI) tract possesses intrinsic neural plexuses that allow a significant degree of autonomy over GI functions, the central nervous system (CNS) provides extrinsic neural inputs that regulate, modulate, and control these functions. While the intestines are capable of functioning in the absence of extrinsic inputs, the stomach and esophagus are much more dependent upon extrinsic neural inputs, particularly from parasympathetic and sympathetic pathways. The sympathetic nervous system exerts a predominantly inhibitory effect upon GI muscle and provides a tonic inhibitory influence over mucosal secretion while, at the same time, regulates GI blood flow via neurally mediated vasoconstriction. The parasympathetic nervous system, in contrast, exerts both excitatory and inhibitory control over gastric and intestinal tone and motility. Although GI functions are controlled by the autonomic nervous system and occur, by and large, independently of conscious perception, it is clear that the higher CNS centers influence homeostatic control as well as cognitive and behavioral functions. This review will describe the basic neural circuitry of extrinsic inputs to the GI tract as well as the major CNS nuclei that innervate and modulate the activity of these pathways. The role of CNS-centered reflexes in the regulation of GI functions will be discussed as will modulation of these reflexes under both physiological and pathophysiological conditions. Finally, future directions within the field will be discussed in terms of important questions that remain to be resolved and advances in technology that may help provide these answers. © 2014 American Physiological Society. Compr Physiol 4: 1339-1368, 2014.
... CCK-1 receptor-deficient animals have been used previously in studies of the regulation of food intake and obesity (Ohta et al., 2000;Bi & Moran, 2002;Moran & Bi, 2006;Bi et al., 2007;Donovan et al., 2007;Kim et al., 2008), and remain promising platforms for the future determination of the role of CCK in those processes. ...
... Alternatively, there may be crosstalk between GHS-R and several gastrointestinal tract peptides, such as cholecystokinin and glucagon-like peptide-1, which also regulate satiety and feeding termination. Furthermore, meal size and feeding frequency may be interdependent; studies examining meal patterns revealed that an increase in meal size may result in decreased feeding frequency (31,32). Consistent with this, the duration of IMI in Ghsr 2/2 -M mice was greater when compared with age-matched WT controls (Fig. 4). ...
Aging is often associated with overweight and obesity. There exists a long-standing debate about whether meal pattern also contributes to the development of obesity. The orexigenic hormone ghrelin regulates appetite and satiety by activating its receptor, growth hormone secretagogue receptor (GHS-R). In mice, circulating ghrelin concentrations and brain GHS-R expression were shown to increase with aging. To assess whether GHS-R regulates feeding pattern during aging, we studied meal patterns for the following cohorts of male mice fed a normal unpurified diet: 1) 3-4 mo, young wild-type (WT) mice; 2) 3-4 mo, young Ghsr-null (Ghsr(-/-)) mice; 3) 12-14 mo, middle-aged WT (WT-M) mice; 4) 12-14 mo, middle-aged Ghsr(-/-) (Ghsr(-/-)-M) mice; 5) 24-26 mo, old WT (WT-O) mice; and 6) 24-26 mo, old Ghsr(-/-) (Ghsr(-/-)-O) mice. Although the total daily food intake of Ghsr(-/-) mice was similar to that of WT controls, Ghsr(-/-)-M and Ghsr(-/-)-O mice had 9% (P = 0.07) and 16% (P < 0.05) less body weight compared with WT-M and WT-O mice, respectively, primarily due to reduced fat mass (P < 0.05, WT-M vs. Ghsr(-/-)-M and WT-O vs. Ghsr(-/-)-O). Intriguingly, Ghsr(-/-)-M mice ate larger meals (on average, Ghsr(-/-)-M mice ate 0.117 g/meal and WT-M mice ate 0.080 g/meal; P < 0.01) and took a longer time to eat (Ghsr(-/-)-M, 196.0 s and WT-M, 128.9 s; P < 0.01), but ate less frequently (Ghsr(-/-)-M, 31.0 times/d and WT-M, 42.3 times/d; P < 0.05) than WT-M controls. In addition, we found that expression of hypothalamic orexigenic peptides, neuropeptide Y (NPY) and agouti-related peptide (AgRP), was relatively lower in aged WT mice (P = 0.09 for NPY and P = 0.06 for AgRP), but anorexic peptide pro-opiomelanocortin (POMC) expression remained unchanged between the WT age groups. Interestingly, old Ghsr(-/-) mice had greater hypothalamic NPY expression (102% higher; P < 0.05) and AgRP expression (P = 0.07) but significantly lower POMC expression (P < 0.05) when compared with age-matched WT-O controls. Thus, our results indicate that GHS-R plays an important role in the regulation of meal pattern and that GHS-R ablation may modulate feeding behavior through the regulation of hypothalamic neuropeptides. Our results collectively suggest that ghrelin receptor antagonism may have a beneficial effect on metabolism during aging.
... Removing vagal input to the hindbrain via chemical or surgical ablation of selective branches can significantly diminish the satiating potency of numerous hormones and signaling molecules controlling energy balance. Similarly, diet-induced obesity may result in reduced sensitivity to satiation signals [e.g., (41)], and increase expression of orexigenic vagal signaling (140), either of which could lead to or exacerbate hyperphagia and obesity. Despite such well-known involvement in energy balance, a paucity of reports exist which address whether vago-vagal signaling alterations contribute to metabolic improvements following RYGB. ...
Arguably the most fundamental physiological systems for all eukaryotic life are those governing energy balance. Without sufficient energy, an individual is unable to survive and reproduce. Thus, an ever-growing appreciation is that mammalian physiology developed a redundant set of neuroendocrine signals that regulate energy intake and expenditure, which maintains sufficient circulating energy, predominantly in the form of glucose, to ensure that energy needs are met throughout the body. This orchestrated control requires cross talk between the gastrointestinal tract, which senses the incoming meal; the pancreas, which produces glycemic counterregulatory hormones; and the brain, which controls autonomic and behavioral processes regulating energy balance. Therefore, this review highlights the physiological, pharmacological, and pathophysiological effects of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide, as well as the pancreatic hormone amylin, on energy balance and glycemic control. Expected final online publication date for the Annual Review of Nutrition Volume 34 is July 17, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
... Methods in which discrete small food items are presented sequentially, as in standard operant behavior protocols, are particularly appealing because they minimize food spoiling behavior for which laboratory mice often show a proclivity. A few such studies have appeared in the recent literature [11][12][13][14][15], but most of these used a low and constant unit price, and did not generate demand functions. In our previous studies using operant response methods in lean and genetically obese mice [10,[15][16][17], we studied the effect of changes in approach cost (we and others [8] previously termed this procurement cost) at a constant but low unit price (previously, consummatory cost); those studies showed that meal parameters in mice are highly sensitive to approach, very similar to results reported in rats [8]. ...
... properties of genes [18]. For example, Brs3, which regulates the latency to intromit during mating, also regulates the latency to attack during territorial aggression; and Cckar, which controls female receptivity during mating, also regulates satiety during feeding [19]. Thus, one can not assert a one-to-one relationship between a genetic mutation and the observed behavioral phenotype without exhaustive phenotypic profiling, which is laborious and seldom carried out. ...
Many complex behaviors are genetically hardwired. Based on previous findings on genetic control of mating and other behaviors in invertebrate and mammalian systems, I suggest that genetic control of complex behaviors is modular: first, dedicated genes specify different behavioral patterns; secondly, separable genetic networks govern distinct behavioral components. I speculate that modular genetic encoding of complex behaviors may in part reflect modularity in brain development and function.
Editor's suggested further reading in BioEssays From songs to synapses: Molecular mechanisms of birdsong memory Abstract
... To address this question, we performed meal tolerance tests using an admixture of corn oil and Ensure-plus (3:17 v/v) that contains 19.4% of the lipids present in equal volume of pure oil. This resulting mixed meal contains 64%kcal from fat and 24.8 kcal/kg BW, which has similar %kcal from fat and total calorie content to a typical meal (200–250 mg) consumed by mice on high-fat diet (HFD) [22,23] (60%kcal from fat and ,26 kcal/kg BW). Thus, we consider the 19.4% lipid load to be at the high end of a physiologically relevant lipid-rich meal (seeTable 1 for comparison of all dietary treatments used). ...
Diacylglycerol acyltransferase-1 (DGAT1) is a potential therapeutic target for treatment of obesity and related metabolic diseases. However, the degree of DGAT1 inhibition required for metabolic benefits is unclear. Here we show that partial DGAT1 deficiency in mice suppressed postprandial triglyceridemia, led to elevations in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) only following meals with very high lipid content, and did not protect from diet-induced obesity. Maximal DGAT1 inhibition led to enhanced GLP-1 and PYY secretion following meals with physiologically relevant lipid content. Finally, combination of DGAT1 inhibition with dipeptidyl-peptidase-4 (DPP-4) inhibition led to further enhancements in active GLP-1 in mice and dogs. The current study suggests that targeting DGAT1 to enhance postprandial gut hormone secretion requires maximal inhibition, and suggests combination with DPP-4i as a potential strategy to develop DGAT1 inhibitors for treatment of metabolic diseases.
... We selected the dose in the acute studies to match the amount of SCFAs consumed in a typical meal in the dietary supplementation experiment. Normal mice were reported to eat approximately 300mg HFD per meal ad libitum, or 10mg/g BW [14,15]. Thus acetate, propionate, and butyrate (supplemented at 3.7 to 5%) were likely consumed at 370 to 500mg/kg per meal in the supplementation study. ...
Short-chain fatty acids (SCFAs), primarily acetate, propionate, and butyrate, are metabolites formed by gut microbiota from complex dietary carbohydrates. Butyrate and acetate were reported to protect against diet-induced obesity without causing hypophagia, while propionate was shown to reduce food intake. However, the underlying mechanisms for these effects are unclear. It was suggested that SCFAs may regulate gut hormones via their endogenous receptors Free fatty acid receptors 2 (FFAR2) and 3 (FFAR3), but direct evidence is lacking. We examined the effects of SCFA administration in mice, and show that butyrate, propionate, and acetate all protected against diet-induced obesity and insulin resistance. Butyrate and propionate, but not acetate, induce gut hormones and reduce food intake. As FFAR3 is the common receptor activated by butyrate and propionate, we examined these effects in FFAR3-deficient mice. The effects of butyrate and propionate on body weight and food intake are independent of FFAR3. In addition, FFAR3 plays a minor role in butyrate stimulation of Glucagon-like peptide-1, and is not required for butyrate- and propionate-dependent induction of Glucose-dependent insulinotropic peptide. Finally, FFAR3-deficient mice show normal body weight and glucose homeostasis. Stimulation of gut hormones and food intake inhibition by butyrate and propionate may represent a novel mechanism by which gut microbiota regulates host metabolism. These effects are largely intact in FFAR3-deficient mice, indicating additional mediators are required for these beneficial effects.
... However, these hormones are coupled with the ANS mechanisms into a complex physiological interaction in such a way that any ANS disorder triggers the physiological unbalance responsible for different gastrointestinal and pancreatobiliary dysfunctions [5,6]. In addition, it has been demonstrated that CCK plays primordial physiological and pathophysiological roles in the motility of the colon [7,8]; in addition, this gastrointestinal hormone crosses the blood brain barrier, at which level it interacts with CCK receptors located at the dorsal raphe serotonergic nucleus DR-5HT and provokes satiety [9,10]. Underlying this physiological phenomenon is the reduction of both gastrointestinal motility and secretions and the inhibition of the distal colon motility. ...
Clinical digestive disorders depend on the non-adequate coupling of functioning of the gastrointestinal tract with that of its affluent systems, namely, the pancreatic exocrine and the hepato-biliary secretions. The secretion of gastrointestinal hormones is monitored by the peripheral autonomic nervous system. However, the latter is regulated by the central nervous system (CNS) circuitry localized at the medullary pontine segment of the CNS. In turn, both parasympathetic and adrenergic medullary circuitries are regulated by the pontine A5 noradrenergic (NA) and the dorsal raphe serotonergic nuclei, respectively. DR-5HT is positively correlated with the C1-Ad medullary nuclei (responsible for adrenal gland secretion), whereas the MR-5HT nucleus is positively correlated with the A5-NA pontomedullary nucleus. The latter is responsible for neural sympathetic activity (sympathetic nerves). Both types of sympathetic activities maintain an alternation with the peripheral parasympathetic branch, which is positively correlated with the enterochromaffin cells that secrete serotonin. Serotonin displays hormonal antagonism to the circulating catecholamines.
... CCK is released from enteroendocrine cells in response to lipids and proteins in the gut lumen and communicates satiety to the NTS via the vagus nerve and its nodose ganglia. Mice lacking the vagal CCK 1 receptor have diminished satiation in response to food intake which results in larger, less frequent meals when on a high fat diet [13]. To determine whether seasonal changes in food intake might involve the gut-vagal-NTS axis, we administered peripheral CCK, which can activate vagal CCK receptors within the gut wall, to squirrels during different seasons and measured the central neural response as indicated by Fos-positive neurons in the NTS. ...
Hibernators that rely on lipids during winter exhibit profound changes in food intake over the annual cycle. The mechanisms that regulate appetite changes in seasonal hibernators remain unclear, but likely consist of complex interactions between gut hormones, adipokines, and central processing centers. We hypothesized that seasonal changes in the sensitivity of neurons in the nucleus tractus solitarius (NTS) to the gut hormone cholecystokinin (CCK) may contribute to appetite regulation in ground squirrels. Spring (SPR), late summer (SUM), and winter euthermic hibernating (HIB) 13-lined ground squirrels (Ictidomys tridecemlineatus) were treated with intraperitoneal CCK (100 μg/kg) or vehicle (CON) for 3h and Fos expression in the NTS was quantified. In CON squirrels, numbers of Fos-positive neurons in HIB were low compared to SPR and SUM. CCK treatment increased Fos-positive neurons in the NTS at the levels of the area postrema (AP) and pre AP during all seasons and at the level of the rostral AP in HIB squirrels. The highest absolute levels of Fos-positive neurons were found in SPR CCK squirrels, but the highest relative increase from CON was found in HIB CCK squirrels. Fold-changes in Fos-positive neurons in SUM were intermediate between SPR and HIB. Thus, CCK sensitivity falls from SPR to SUM suggesting that seasonal changes in sensitivity of NTS neurons to vagally-derived CCK may influence appetite in the active phase of the annual cycle in hibernating squirrels. Enhanced sensitivity to CCK signaling in NTS neurons of hibernators indicates that changes in gut-brain signaling may contribute to seasonal changes in food intake during the annual cycle.
... Previous studies reported a decrease in meal size of liquid food intake in lean mice [45] and an increased latency to eat in obese ob/ob mice [46] following 8 or 18 µg/kg CCK-8 in mice fasted for 1.5–4.5 h or 23 h, respectively. In line with these findings, CCK 1 receptor knockout mice fed a high fat diet consumed larger meals and had a decreased latency to start eating following a 6-h fast [47]. Using the automated episodic food intake monitoring system, sst 2 agonist injected icv was found to increase food intake during the first 4 h post injection with values similar to those obtained by manual assessment. ...
We recently reported that the oligosomatostatin receptor agonist, ODT8-SST increases food intake in rats via the somatostatin 2 receptor (sst(2)). We characterized ingestive behavior following intracerebroventricular (icv) injection of a selective sst(2) agonist in freely fed mice during the light phase. The sst(2) agonist (0.01, 0.03, 0.1, 0.3 or 1μg/mouse) injected icv under short inhalation anesthesia dose-dependently increased cumulative light phase food intake over 4h compared to vehicle with a 3.1-times increase at 1μg/mouse (p<0.05). Likewise, the sst(2,3,5) agonist octreotide (0.3 or 1μg/mouse) dose-dependently increased 4-h food intake, whereas selective sst(1) or sst(4) agonists at 1μg/mouse did not. In vehicle-treated mice, high fat diet increased caloric intake/4h by 2.8-times compared to regular diet (p<0.05) and values were further increased 1.4-times/4h by the sst(2) agonist. Automated continuous assessment of food intake established a 6.6-times higher food intake during the dark phase due to increased number of meals, meal size, meal duration and rate of ingestion compared to non-treated mice during the light phase. During the first 4h post icv sst(2) agonist injection, mice had a 57% increase in number of meals with a 60% higher rate of ingestion, and a 61% reduction in inter-meal intervals, whereas meal sizes were not altered compared to vehicle. These data indicate that the activation of brain sst(2) receptors potently stimulates the light phase ingestive behavior under basal or high fat diet-stimulated conditions in mice. The shortened inter-meal interval suggests an inhibitory effect of the sst(2) agonist on "satiety", whereas "satiation" is not altered as indicated by normal meal size.
... In mice, a reduction in CCK pathway signaling causes feeding defects (meal size increases associated with compensatory reductions in meal frequency) that are similar to those we see in leuc and lkr mutants [38]. This probably does not represent a conserved pathway, since leucokinin and its receptor have little sequence homology with mammalian CCK pathway components. ...
Total food intake is a function of meal size and meal frequency, and adjustments to these parameters allow animals to maintain a stable energy balance in changing environmental conditions. The physiological mechanisms that regulate meal size have been studied in blowflies but have not been previously examined in Drosophila.
Here we show that mutations in the leucokinin neuropeptide (leuc) and leucokinin receptor (lkr) genes cause phenotypes in which Drosophila adults have an increase in meal size and a compensatory reduction in meal frequency. Because mutant flies take larger but fewer meals, their caloric intake is the same as that of wild-type flies. The expression patterns of the leuc and lkr genes identify small groups of brain neurons that regulate this behavior. Leuc-containing presynaptic terminals are found close to Lkr neurons in the brain and ventral ganglia, suggesting that they deliver Leuc peptide to these neurons. Lkr neurons innervate the foregut. Flies in which Leuc or Lkr neurons are ablated have defects identical to those of leucokinin pathway mutants.
Our data suggest that the increase in meal size in leuc and lkr mutants is due to a meal termination defect, perhaps arising from impaired communication of gut distension signals to the brain. Leucokinin and the leucokinin receptor are homologous to vertebrate tachykinin and its receptor, and injection of tachykinins reduces food consumption. Our results suggest that the roles of the tachykinin system in regulating food intake might be evolutionarily conserved between insects and vertebrates.
... whether meal size or meal frequency were affected) [75]. Such additional studies might be pertinent given that the normal food intake of Cck A r-deficient mice is due to longer bouts of feeding with a compensatory reduction in meal frequency [76]. ...
The rise in the global prevalence of human obesity has emphasized the need for a greater understanding of the physiological mechanisms that underlie energy homeostasis. Numerous circulating nutritional cues and central neuromodulatory signals are integrated within the brain to regulate both short- and long-term nutritional state. The central melanocortin system represents a crucial point of convergence for these signals and, thus, has a fundamental role in regulating body weight. The melanocortin ligands, synthesized in discrete neuronal populations within the hypothalamus and brainstem, modulate downstream homeostatic signalling via their action at central melanocortin-3 and -4 receptors. Intimately involved in both ingestive behaviour and energy expenditure, the melanocortin system has garnered much interest as a potential therapeutic target for human obesity.
... Methods in which discrete small food items are presented sequentially, as in standard operant behavior protocols, are particularly appealing because they minimize food spoiling behavior for which laboratory mice often show a proclivity. A few such studies have appeared in the recent literature [11][12][13][14][15], but most of these used a low and constant unit price, and did not generate demand functions. In our previous studies using operant response methods in lean and genetically obese mice [10,[15][16][17], we studied the effect of changes in approach cost (we and others [8] previously termed this procurement cost) at a constant but low unit price (previously, consummatory cost); those studies showed that meal parameters in mice are highly sensitive to approach, very similar to results reported in rats [8]. ...
Several field and experimental studies have investigated the behavioral economics of food intake. In the laboratory, operant behavior has been used to emulate cost and to generate demand functions that express the relationship between the price of food and amount consumed. There have been few such studies of motivated food seeking and intake in mice, and none has reported demand functions. Using albino (CD1) male mice, the present study compares food intake and meal patterns across a series of ratio cost schedules. The first experiment examined unit price. A closed economy was used in which the mice were in the test chambers for 23 h/day and earned all of their food via either a nose poke or lever press response under fixed (FUP5, FUP10, FUP25, FUP50), variable (VUP10, VUP20, VUP50), and progressive (PUP1.25, PUP1.5, PUP1.75) unit prices. Mice were run for 4 days at each cost. There were no consistent differences between the first and last day indicating that behavioral adjustments to schedule changes occurred rapidly. When averaged across all price schedules, mice in the nose poke group consumed more food than their lever press counterparts but the overall shapes of the demand curves did not differ between the two operant responses, with intake decreasing as price increased. The number of meals taken per day differed between two meal-defining criteria that we applied, and there were some differences between the types of unit price schedule. In the second experiment, approach cost in the form of nose poke responses was required to activate a response device (lever) on which a fixed unit price for food was in force. These approach and unit costs were varied systematically. Meal number decreased, and meal size increased, with increasing approach cost even though nose pokes accounted for only a small fraction of the total response activity. Thus, meal patterns in mice are sensitive to approach cost while total amount consumed is more sensitive to unit price. These data are discussed in terms of the concept of foraging cost as either a unitary or a multidimensional variable.
Context:
The glucagon-like peptide-1 receptor (GLP-1R) agonist semaglutide (SEMA) produces 15% weight loss when chronically administered to humans with obesity.
Methods:
In 2 separate experiments, rats received daily injections of either vehicle (VEH) or SEMA starting at 7 µg/kg body weight (BW) and increasing over 10 days to the maintenance dose (70 µg/kg-BW), emulating clinical dose escalation strategies.
Results:
During dose escalation and maintenance, SEMA rats reduced chow intake and bodyweight. Experiment 2 meal pattern analysis revealed that meal size, not number, mediated these SEMA-induced changes in chow intake. This suggests SEMA affects neural processes controlling meal termination and not meal initiation. Two-bottle preference tests (vs water) began after 10 to 16 days of maintenance dosing. Rats received either an ascending sucrose concentration series (0.03-1.0 M) and 1 fat solution (Experiment 1) or a 4% and 24% sucrose solution in a crossover design (Experiment 2). At lower sucrose concentrations, SEMA-treated rats in both experiments drank sometimes >2× the volume consumed by VEH controls; at higher sucrose concentrations (and 10% fat), intake was similar between treatment groups. Energy intake of SEMA rats became similar to VEH rats. This was unexpected because GLP-1R agonism is thought to decrease the reward and/or increase the satiating potency of palatable foods. Despite sucrose-driven increases in both groups, a significant bodyweight difference between SEMA- and VEH-treated rats remained.
Conclusion:
The basis of the SEMA-induced overconsumption of sucrose at lower concentrations relative to VEH controls remains unclear, but the effects of chronic SEMA treatment on energy intake and BW appear to depend on the caloric sources available.
High prevalence of obesity is attributable in part to consumption of highly palatable, fat-rich foods. However, the mechanism controlling dietary fat intake is largely unknown. In this study we investigated the role of brain-derived neurotrophic factor (BDNF) in the control of dietary fat intake in a mouse model that mimics the common human Val-to-Met (Val66Met) polymorphism that impairs BDNF release via the regulated secretory pathway. BdnfMet/Met mice gained weight much faster than WT mice and developed severe obesity due to marked hyperphagia when they were fed HFD. Hyperphagia in these mice got worse when the fat content in a diet was increased. Conversely, mice lacking leptin exhibited similar hyperphagia on chow and HFD. When two diets were provided simultaneously, WT and BdnfMet/Met mice showed comparable preference for the more palatable diet rich in either fat or sucrose, indicating that increased hyperphagia on fat-rich diets in BdnfMet/Met mice is not due to enhanced hedonic drive. In support of this interpretation, WT and BdnfMet/Met mice increased calorie intake to a similar extent during the first day after chow was switched to HFD; however, WT mice decreased HFD intake faster than BdnfMet/Met mice in subsequent days. Furthermore, we found that refeeding after fasting or nocturnal feeding with HFD activated TrkB more strongly than with chow in the hypothalamus of WT mice, whereas TrkB activation under these two conditions was greatly attenuated in BdnfMet/Met mice. These results indicate that satiety factors generated during HFD feeding induce BDNF release to suppress excess dietary fat intake.
L’intestin joue un rôle clé dans le contrôle de l’homéostasie énergétique. Les entérocytes sont des cellules polarisées qui permettent les échanges entre la lumière intestinale (membrane apicale) et le compartiment lymphatique et sanguin (membrane baso-latérale). Dans cette thèse, nous nous sommes particulièrement intéressés au contrôle par les entérocytes de deux processus liés au métabolisme des lipides et du cholestérol : l’excrétion trans-intestinale de cholestérol (TICE) et l’absorption des lipides alimentaires.Très récemment, il a été montré que l’intestin contribue à 20-30% de l’excrétion fécale du cholestérol chez la souris. Ce mécanisme, appelé TICE, implique le passage direct du cholestérol provenant de la circulation sanguine à travers les entérocytes vers les fèces. De par son caractère modulable par des substances pharmacologiques comme l’ézétimibe et les statines, le TICE représente une cible thérapeutique potentielle pour corriger les dyslipidémies athérogènes du diabétique. Cependant, les mécanismes moléculaires gouvernant le transport rétrograde du cholestérol (du pôle baso-latéral au pôle apical) dans l’entérocyte lors du TICE, sont complètement inconnus. Dans une première étude, nous avons mis en évidence la lignée entérocytaire humaine Caco-2/TC7 comme un modèle d’étude des processus trans-entérocytaires liés au TICE. Nous avons d’abord montré que suite à l’incubation avec du plasma humain dans le compartiment baso-latéral et des micelles lipidiques dans le compartiment apical, les cellules Caco-2/TC7 miment des caractéristiques du TICE in vivo. De plus, grâce à ce modèle in vitro, nous avons pu identifier les microtubules comme acteurs nécessaires au transport rétrograde du cholestérol dans l’entérocyte. Dans une seconde étude, nous nous sommes intéressés au contrôle par le récepteur nucléaire Rev-erbα de la production des chylomicrons (CM) par les entérocytes. En effet, bien qu’essentiellement vue comme la conséquence d’une clairance retardée, des données émergentes présentent la surproduction de CM par l’intestin comme un contributeur majeur de la dyslipidémie chez l’insulino-résistant. Il existe une balance, au sein de l’entérocyte, entre l’utilisation des lipides absorbés pour un stockage transitoire sous forme de gouttelettes lipidiques (GL) cytosoliques ou pour l’assemblage de lipoprotéines riches en triglycérides (LRT). Le récepteur nucléaire Rev-erbα est un répresseur transcriptionnel impliqué dans le métabolisme énergétique et le rythme circadien. Rev-erbα contrôle particulièrement le métabolisme lipidique au niveau du foie et le catabolisme des LRT. Pour cette seconde étude, une lignée Caco-2/TC7 invalidée pour Rev-erbα (sh Rev-erbα) a donc été développée par infection lentivirale et différenciée sur insert. Les résultats indiquent que suite à l’incubation avec des micelles lipidiques dans le compartiment apical, les cellules Caco-2/TC7 sh Rev-erbα sécrètent plus de LRT dans le milieu baso-latéral et stockent moins de lipides sous la forme de GL cytosoliques. De plus, la lignée Caco-2/TC7 sh Rev-erbα présente une activité lipophagique plus importante et l’inhibition de l’autophagie par la bafilomycine dans cette lignée restaure la sécrétion baso-latérale de LRT et le stockage intracellulaire de GL aux mêmes niveaux que ceux de la lignée sh control. Cette seconde étude montre donc que l’invalidation de Rev-erbα dans l’entérocyte entraîne une augmentation de la mobilisation des lipides des GL via le processus de la lipophagie résultant en une augmentation de la sécrétion de LRT. Notre hypothèse est que Rev-erbα joue un rôle clé dans le contrôle de la balance GL/LRT et donc de la triglycéridémie post-prandiale.Les deux études présentées dans cette thèse permettent une meilleure compréhension des mécanismes liés au contrôle du métabolisme lipidique par l’intestin et mettent ainsi en avant l’intestin comme une cible thérapeutique potentielle pour corriger les dyslipidémies du diabétique.
After Roux-en-Y gastric bypass surgery (RYGB), rats tend to reduce consumption of high-sugar and/or high-fat foods over time. Here, we sought to investigate the behavioral mechanisms underlying these intake outcomes. Adult female rats were provided a cafeteria diet comprised of five palatable foodstuffs varying in sugar and fat content and intake was monitored continuously. Rats were then assigned to either RYGB, or one of two control (CTL) groups: sham surgery or a nonsurgical control group receiving the same prophylactic iron treatments as RYGB rats. Post-sur-gically, all rats consumed a large first meal of the cafeteria diet. After the first meal, RYGB rats reduced intake primarily by decreasing the meal sizes relative to CTL rats, ate meals more slowly, and displayed altered nycthemeral timing of intake yielding more daytime meals and fewer nighttime meals. Collectively, these meal patterns indicate that despite being motivated to consume a cafeteria diet after RYGB, rats rapidly learn to modify eating behaviors to consume foods more slowly across the entire day. RYGB rats also altered food preferences, but more slowly than the changes in meal patterns, and ate proportionally more energy from complex carbohydrates and protein and proportionally less fat. Overall, the pattern of results suggests that after RYGB rats quickly learn to adjust their size, eating rate, and distribution of meals without altering meal number and to shift their macronutrient intake away from fat; these changes appear to be more related to postingestive events than to a fundamental decline in the palatability of food choices.
The communication between the gut and the brain is important for the control of energy homeostasis. In response to food intake, enteroendocrine cells secrete gut hormones which ultimately suppress appetite through centrally‐mediated processes. Increasing evidence implicates the vagus nerve as an important conduit in transmitting these signals from the gastrointestinal tract to the brain. Studies have demonstrated that many of the gut hormones secreted from enteroendocrine cells signal through the vagus nerve, and the sensitivity of the vagus to these signals is regulated by feeding status. Furthermore, evidence suggests that a reduction in the ability of the vagus nerve to respond to the switch between a “fasted” and “fed” state, retaining sensitivity to orexigenic signals when fed or a reduced ability to respond to satiety hormones, may contribute to obesity.
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Control of food intake and body weight involves multiple pathways and body systems. Recent evidence, in part from the effectiveness of bariatric surgical procedures in treatment of obesity and metabolic disease, but also from the availability of transgenic mice, suggests that the gut can play a predominant role in the long-term regulation of food intake, appetitive behavior, and overall energy balance. Here we review the mechanisms in the gut and the pathways from the gut to the brain that can influence these processes. Information is also included on how these mechanisms and gut-brain pathways may change in obesity and metabolic disease, and the role the gut microbiota might play in mediating these changes.
The regulation of feeding behavior consists of a complex interaction between nutrients in the blood, peripheral hormones, neuropeptides and a number of different brain areas. Together, this system works to initiate feeding when feeling hungry and to stop eating when feeling satiated, thereby maintaining a healthy body weight in normal weight individuals. However, anorexia patients persistently override signals of hunger, whereas obese people continue to override signals of satiety. The rewarding properties of food and motivation related to food are therefore also important factors in the regulation of feeding behavior. In this chapter we will review the role of different genes in hunger and satiety signaling as well as food reward and food-motivated behavior. We will first describe the animal models that have been used to study genes involved in feeding behavior and then review the knowledge obtained from genetic studies in humans.
Leptin, ghrelin and neuropeptide W (NPW) modulate vagal afferent activity, which may underlie their appetite regulatory actions. High fat diet (HFD)-induced obesity induces changes in the plasma levels of these peptides and alters the expression of receptors on vagal afferents. We investigated homologous and heterologous receptor regulation by leptin, ghrelin and NPW. Mice were fed (12-weeks) a standard laboratory diet (SLD) or HFD. Nodose ganglia were cultured overnight in the presence or absence of each peptide. Leptin (LepR), ghrelin (GHS-R), NPW (GPR7) and cholecystokinin type-1 (CCK1R) receptor mRNA, and the plasma leptin, ghrelin and NPW levels were measured. SLD: leptin reduced LepR, GPR7, increased GHS-R and CCK1R mRNA; ghrelin increased LepR, GPR7, CCK1R, and decreased GHS-R. HFD: leptin decreased GHS-R and GPR7, ghrelin increased GHS-R and GPR7. NPW decreased all receptors except GPR7 which increased with HFD. Plasma leptin was higher and NPW lower in HFD. Thus, HFD-induced obesity disrupts inter-regulation of appetite regulatory receptors in vagal afferents.
This study investigated eating pattern in weaning female Sprague-Dawley rats fed high-fat diets of varying fatty acid composition. Rats were randomly assigned to canola- or butter-based diets, and their eating pattern and body weight were assessed at early exposure (P1) and following 3 weeks (P2). In P2, a lower 24-h intake, smaller meal size, and shorter nocturnal meal duration were found in both dietary groups. In both groups, 24-h intakes were comparable throughout the experiment; however, butter-fed rats gained more weight. With canola feeding, P1 nocturnal intake was greater than diurnal intake, but intakes were comparable in P2. Butter-fed rats had similar diurnal and nocturnal intakes in P1; in P2, diurnal was greater than nocturnal intake. Canola-fed rats had similar diurnal and nocturnal meal size and eating rate, whereas butter-fed rats ate larger meals at a higher rate in the light than in the dark phase. The present work brings new knowledge about exposure to high-fat diets early in life and later development of obesity.
The manuscript, "The role of cholecystokinin 1 receptor in prolactin inhibited gastric emptying of male rat," is a well designed study.1 I would like to congratulate the authors for their excellent work. In the acute hyperprolactinemic rats, the authors found that prolactin inhibited the gastric emptying dose-dependently and increased the level of cholecystokinin (CCK). The selective CCK1 receptor antagonist restored the delayed gastric emptying induced by prolactin although it had no effect on gastric emptying, which suggested that prolactin worked via the CCK1 receptor. In the chronic hyperprolactinemic rats, similar increase of CCK level and delayed gastric emptying was also found. Previous studies have demonstrated the effect of prolactin on gastrointestinal motility in lactating rodent.2 Increases in gastric emptying and gastrointestinal transit correlated with lactation and plasma prolactin levels. In this study, the inhibited gastric emptying was found in hyperprolactinemic male rats, which suggested that the effect of prolactin differed by gender and species. This result may provide a guide for future study and clinical use. The reviewer has some comments: (1) The purpose of experiments with chronic hyperprolactinemic rats, I suppose, is to confirm that chronic and exogenous prolactin is also capable of inhibiting the gastric emptying via CCK. However, it has been reported that prolactin can stimulate the secretion of hormones such as testosterone etc.3 It is also demonstrated that the sexual hormones have the ability of regulating the gastric emptying.4,5 Administration of estrogen inhibits the rat gastric emptying while progesterone enhances the gastric emptying. Therefore, a further session including the CCK1 receptor antagonist should be investigated to confirm that the exogenous prolactin also act through the CCK. (2) As the authors mentioned, prolactin showed a reversed effect in lactating rats. For more reliable result presenting different effects of prolactin on gastric emptying in different genders, it is better to perform an additional experiment involving no-lactating female rats since the sexual hormones during lactation are completely different from non-lactating period and the hormones may have effect on gastric emptying, such as progestrone etc.6 (3) CCK is an important hormone for regulating the food intake and satiety sensation.7-9 CCK induces reduction of food intake dose-dependently and CCK1 receptor is involved in regulating caloric intake. In the experiments of chronic hyperprolactinemic rats, the author did not show whether there were any changes in the food intake and weight in the rats or not. If yes, it might enlighten some new use of prolactin, such as in obesity.
Background and aims:
Diet-induced obesity (DIO) is an excellent model for examining human obesity comprising both genotypic and environmental (diet) factors. Decreased responsiveness to peripheral satiety signaling may be responsible for the hyperphagia in this model. In this study, we investigated responses to nutrient-induced satiation in outbred DIO and DIO-resistant (DR) rats fed a high-energy/high-fat (HE/HF) diet as well as intestinal satiety peptide content, intestinal nutrient-responsive receptor abundance and vagal anorectic receptor expression.
Methods:
Outbred DIO and DR rats fed a HE/HF diet were tested for short-term feeding responses following nutrient (glucose and intralipid (IL)) gastric loads. Gene and protein expressions of intestinal satiety peptides and fatty acid-responsive receptors were examined from isolated proximal intestinal epithelial cells and cholecystokinin-1 receptor (CCK-1R) and leptin receptor (LepR) mRNA from the nodose ganglia of DIO and DR animals.
Results:
DIO rats were less responsive to IL- (P<0.05) but not glucose-induced suppression of food intake compared with DR rats. DIO rats exhibited decreased CCK, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1; P<0.05 for each) protein expression compared with DR rats. Also, DIO rats expressed more G-protein-coupled receptor 40 (GPR40; P<0.0001), GPR41 (P<0.001) and GPR120 (P<0.01) relative to DR rats. Finally, there were no differences in mRNA expression for CCK-1R and LepR in the nodose ganglia of DIO and DR rats.
Conclusions:
Development of DIO may be partly due to decreased fat-induced satiation through low levels of endogenous satiety peptides, and changes in intestinal nutrient receptors.
Central nervous system (CNS) receives peripheral relevant information that are able to regulate individual's energy balance through metabolic, neural, and endocrine signals. Ingested nutrients come into contact with multiple sites in the gastrointestinal tract that have the potential to alter peptide and neural signaling. There is a strong relationship between CNS and those peripheral signals (as gastrointestinal hormones) in the control of food intake. The purpose of this review is to give updated information about the role of gut hormones as mediators of feeding behavior and of different nutrients in modulating gut hormones production. The role of gut hormones in the pathogenesis of emerging diseases as obesity and non-alcoholic fatty liver disease (NAFLD) is also discussed together with the possible role of these peripheral signals as targets of future therapeutic options.
Two views are being debated around fat-rich food and appetite regulation. One is that fat intake has a weak satiety-signaling property, with the consequence being a passive overconsumption of fat-rich food, in turn leading to obesity (Westerterp, 2006). The other view is that fat intake is tightly regulated through specific signals, which when overstimulated leads to aversion (Jebb et al., 2006). Fat intake depends not only on the quantity but more importantly on the quality of fat ingested, whether it is saturated, monounsaturated, or polyunsaturated fat (Casas-Agustench et al., 2008). Another important feature relates to whether the fat is eaten with sucrose or with something that has a sweet taste (Erlanson-Albertsson, 2005a). In general this will lead to a blunted response. Endocannabinoids released after palatable food ingestion, such as food containing fat and sucrose, will promote hunger and energy storage. The following hormones have been found to regulate the appetite for fat. Galanin (Gaysinskaya et al., 2007), agouti-related peptide (AgRP) (Tracy et al., 2007), and ghrelin (Shimbara et al., 2004) stimulate fat intake, while enterostatin (Berger et al., 2004), apolipoprotein A-IV (Apo A-IV) (Tso and Liu, 2004a), peptide YY (PYY) (Boey et al., 2008), cholecystokinin (CCK) (Beglinger and Degen, 2004), and neuropeptide Y (NPY) (Primeaux et al., 2005) inhibit fat intake. Both galanin (Schneider et al., 2007) and ghrelin (Jerlhag et al., 2007) also stimulate the intake of ethanol, via pathways involving a link to the reward system. The inhibition of fat intake occurs through reduced gastric emptying and serotonin release (Ritter, 2004). A proper satiety for fat is possible only with complete fat digestion, fatty acids being important to release satiety hormones (Feinle-Bisset et al., 2005). For proper control of fat intake, fat digestion needs to be retarded without being inhibited (Albertsson et al., 2007). Why we overeat fat? Energy dense. Gastrointestinal processing too rapid. Satiety signals too weak. Hunger signals too strong.
The general objective of this thesis was to investigate the effects of high-fat diets (67% of energy) containing high (butter), moderate (lard) or low levels (canola oil) of saturated fatty acids (SFA) on food intake, eating pattern, obesity development and its reversal in female Sprague-Dawley rats. Periods of 26 or 50 days of high-fat feeding were used in adult rats, and of 7 or 28 days in weaning animals; in adult rats, obesity reversal was evaluated following 28 days of low-fat feeding (27% of energy) and after 32 days of low-fat food restriction. The findings showed that: 1- Exposure for 26 days to low- or moderate-SFA high-fat diets resulted in comparable intake and body weight, while 26 or 50 days of feeding with high-SFA diet led to greater intake and body weight than low-SFA diet; 2- Obesity that developed with SFA-rich diet was accompanied with failure to adjust intake based on diet energy density and preserving body fat even after weight loss; 3- Weight loss was achieved by offering a restricted amount of a low-fat diet but not with ad libitum feeding; 4- Altered diurnal eating pattern was found with high-fat feeding and characterized by a smaller number of meals, longer inter-meal interval and enhanced satiety ratio, regardless of obesity status; SFA-rich diet fed obese rats ate larger meals overall; 5- In weaning rats, three-week exposure to high-fat diets shifted intake toward the light phase; this response was more prominent with high- than with low-SFA diet and was accompanied with greater body weight and altered eating pattern - larger diurnal than nocturnal meals were consumed at a higher rate - rather than overeating. In conclusion, in adult female rats, a SFA-rich diet resulted in overeating and obesity, relative to a low-SFA diet. In weaning female rats, a SFA-rich diet also led to a greater body weight gain, but without overeating. These results underscore the role dietary fatty acid profile may play in developing obesity in early and adult life. L'objectif général de cette thèse était d'examiner les effets de régimes riches en gras alimentaire (67% de l'énergie) à haute (beurre), moyenne (saindoux) ou faible (huile de canola) teneur en acides gras saturés (SFA) sur la consommation alimentaire, la séquence prandiale et nycthémérale, le développement de l'obésité et son inversion chez des rates Sprague-Dawley. Des rates adultes ont été exposées à un régime riche en graisse pendant des périodes de 26 ou 50 jours, et des périodes de 7 ou 28 jours pour des rates sevrées. Chez les animaux adultes, le renversement de l'obésité à été évalué après 28 jours avec un régime faible en graisses (27% de l'énergie) et suite à 32 jours avec un régime alimentaire restreint et faible en graisse. Les résultats de ces travaux ont montré que: 1- L'exposition durant 26 jours à un régime alimentaire riche en graisse mais à faible ou moyenne teneur en SFA a produit une consommation alimentaire et un poids corporel comparables, tandis que 26 ou 50 jours d'exposition au régime alimentaire riche en graisse et à haute teneur en SFA a mené à une ingestion alimentaire plus importante et un poids corporel plus élevé qu'un régime alimentaire à faible teneur en SFA; 2- L'obésité développée avec le régime alimentaire à haute teneur en SFA était accompagnée d'une incapacité d'ajuster l'ingestion alimentaire en fonction de la densité énergétique du régime et de la conservation du gras corporel même après la perte de poids; 3- Une perte de poids a été rendue possible avec un régime faible en graisse et offert en quantité restreinte mais pas avec l'alimentation à volonté; 4- Un régime riche en graisse a modifié la séquence prandiale diurne, avec une diminution du nombre de repas, un intervalle entre chaque repas plus long et une satiété accrue sans égard à l'état de l'obésité; dans l'ensemble, les animaux obèses nourris avec le régime alimentaire à haute teneur en SFA ont ingéré de plus gros repas; 5- Chez les rates sevrées, après trois semaines d'exposition à un régime riche en graisse, l'ingestion s'est déplacée vers la phase lumineuse; cette réaction était plus importante avec le régime à haute teneur en SFA qu'avec le régime à faible teneur en SFA. Cette réponse était accompagnée d'un poids corporel plus élevé et d'une modification de la séquence alimentaire - de plus gros repas étaient consommés plus rapidement durant le jour qu'au cours de la nuit - mais sans surconsommation alimentaire. En conclusion, chez les rates adultes, un régime riche en gras alimentaire à haute teneur en SFA a produit une surconsommation alimentaire et de l'obésité, en comparaison avec un régime alimentaire à faible teneur en SFA. Chez les rates sevrées le régime à haute teneur en SFA a aussi produit un poids corporel plus élevé mais sans surconsommation. Ces résultats soulignent le rôle que peuvent jouer les acides gras alimentaires dans le développement de l'obésité tôt dans la vie et à l'âge adulte.
Vagal afferent neurons (VAN) express the cholecystokinin (CCK) type 1 receptor (CCK₁R) and, as predicted by the role of CCK in inducing satiation, CCK₁R⁻/⁻ mice ingest larger and longer meals. However, after a short fast, CCK₁R⁻/⁻ mice ingesting high fat (HF) diets initiate feeding earlier than wild-type mice. We hypothesized that the increased drive to eat in CCK₁R⁻/⁻ mice eating HF diet is mediated by ghrelin, a gut peptide that stimulates food intake. The decrease in time to first meal, and the increase in meal size and duration in CCK₁R⁻/⁻ compared to wild-type mice ingesting high fat (HF) diet were reversed by administration of GHSR1a antagonist D-(Lys3)-GHRP-6 (p<0.05). Administration of the GHSR1a antagonist significantly increased expression of the neuropeptide cocaine and amphetamine-regulated transcript (CART) in VAN of HF-fed CCK₁R⁻/⁻ but not wild-type mice. Administration of the GHSR1a antagonist decreased neuronal activity measured by immunoreactivity for fos protein in the nucleus of the solitary tract (NTS) and the arcuate nucleus of both HF-fed wild-type and CCK₁R⁻/⁻ mice. The data show that hyperphagia in CCK₁R⁻/⁻ mice ingesting HF diet is reversed by blockade of the ghrelin receptor, suggesting that in the absence of the CCK₁R, there is an increased ghrelin-dependent drive to feed. The site of action of ghrelin receptors is unclear, but may involve an increase in expression of CART peptide in VAN in HF-fed CCK₁R⁻/⁻ mice.
Defective melanocortin signaling causes hyperphagic obesity in humans and the melanocortin-4 receptor knockout mouse (MC4R(-/-)). The human disease most commonly presents, however, as haploinsufficiency of the MC4R. This study validates the MC4R(+/-) mouse as a model of the human disease in that, like the MC4R(-/-), the MC4R(+/-) mouse also exhibits a sustained hyperphagic response to dietary fat. Furthermore, both saturated and monounsaturated fats elicit this response. N-acylphosphatidylethanolamine (NAPE) is a signaling lipid induced after several hours of high-fat feeding, that, if dysregulated, might explain the feeding behavior in melanocortin obesity syndrome. Remarkably, however, MC4R(-/-) mice produce elevated levels of NAPE and are fully responsive to the anorexigenic activity of NAPE and oleoylethanolamide. Interestingly, additional differences in N-acylethanolamine (NAE) biochemistry were seen in MC4R(-/-) animals, including reduced plasma NAE levels and elevated hypothalamic levels of fatty acid amide hydrolase expression. Thus, while reduced expression of NAPE or NAE does not explain the high-fat hyperphagia in the melanocortin obesity syndrome, alterations in this family of signaling lipids are evident. Analysis of the microstructure of feeding behavior in response to dietary fat in the MC4R(-/-) and MC4R(+/-) mice indicates that the high-fat hyperphagia involves defective satiation and an increased rate of food intake, suggesting defective satiety signaling and enhanced reward value of dietary fat.
Cholecystokinin (CCK) has long been implicated in body energetics, first as a gastrointestinal hormone assisting fat utilization and later as a neuropeptide acting either peripherally or centrally in the regulation of body mass. In the present review the thermoregulatory role of CCK peptides is reviewed with special emphasis on two types of responses, that is hyperthermia (fever) or hypothermia. Central microinjection of CCK in rats induces a thermogenic response that can be attenuated by CCK2 receptor antagonists, but some authors observed a mild hypothermia. By contrast to its central fever-inducing effect, CCK-8 elicits a dose-dependent hypothermia on peripheral injection probably acting on CCK1 receptors in rodents exposed to cold. It is suggested that neuronal CCK may have a specific role in the development of hyperthermia and endogenous CCK-ergic mechanisms could contribute to the mediation of fever. Recent evidence in rodents lacking either of the CCK receptors appears to support the fever-mediating role of the peptide. In particular, CCK2 receptors seem to be involved in the development of endotoxin fever, while the role of CCK1 receptors could be more complex. In line with that idea, rats lacking functional CCK1 receptors show an exaggerated fever response, a phenomenon that may be associated with a trait different from the absence of this receptor set. The relationship between the putative CCK-ergic febrile mechanism and the established central prostaglandin mediation is also discussed.
Recent studies have shown that the rate of aging can be modulated by diverse interventions. Dietary restriction is the most widely used intervention to promote longevity; however, the mechanisms underlying the effect of dietary restriction remain elusive. In a previous study, we identified two novel genes, nlp-7 and cup-4, required for normal longevity in Caenorhabditis elegans. nlp-7 is one of a set of neuropeptide-like protein genes; cup-4 encodes an ion-channel involved in endocytosis by coelomocytes. Here, we assess whether nlp-7 and cup-4 mediate longevity increases by dietary restriction. RNAi of nlp-7 or cup-4 significantly reduces the life span of the eat-2 mutant, a genetic model of dietary restriction, but has no effect on the life span of long-lived mutants resulting from reduced insulin/IGF-1 signaling or dysfunction of the mitochondrial electron transport chain. The life-span extension observed in wild-type N2 worms by dietary restriction using bacterial dilution is prevented significantly in nlp-7 and cup-4 mutants. RNAi knockdown of genes encoding candidate receptors of NLP-7 and genes involved in endocytosis by coelomocytes also specifically shorten the life span of the eat-2 mutant. We conclude that two novel pathways, NLP-7 signaling and endocytosis by coelomocytes, are required for life extension under dietary restriction in C. elegans.
Food intake and body weight are determined by a complex interaction of regulatory pathways. To elucidate the contribution of the endogenous peptide cholecystokinin, mice lacking functional cholecystokinin-A receptors were generated by targeted gene disruption. To explore the role of the cholecystokinin-A receptor in mediating satiety, food intake of cholecystokinin-A receptor(-/-) mice was compared with the corresponding intakes of wild-type animals and mice lacking the other known cholecystokinin receptor subtype, cholecystokinin-B/gastrin. Intraperitoneal administration of cholecystokinin failed to decrease food intake in mice lacking cholecystokinin-A receptors. In contrast, cholecystokinin diminished food intake by up to 90% in wild-type and cholecystokinin-B/gastrin receptor(-/-) mice. Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor. To explore the long-term consequences of either cholecystokinin-A or cholecystokinin-B/gastrin receptor absence, body weight as a function of age was compared between freely fed wild-type and mutant animals. Both cholecystokinin-A and cholecystokinin-B/gastrin receptor(-/-) mice maintained normal body weight well into adult life. In addition, each of the two receptor(-/-) strains had normal pancreatic morphology and were normoglycemic. Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight.
Analysis of feeding patterns in rats showed that the amount of food eaten in relatively long intervals (24-72 hr) was correlated with mean meal size and was essentially uncorrelated with meal frequency. Similarly, the regulatory adjustment in daily food intake occurring in response to changes in environmental temperature was shown to be the result of an adjustment in mean meal size, with no change in meal frequency. On the other hand, the amount of food eaten in relatively short intervals (3-12 hr) was shown to be more highly correlated with meal frequency than with mean meal size, and a reliable correlation between meal size and the postmeal interval was obtained. It was also shown that the meal size/postmeal interval regression equation predicts the long-term relation between mean meal size and the amount of food eaten. Take together, these results indicate that meal frequency is controlled largely by short-term regulatory signals and that at least some long-term regulatory signals affect meal size directly.
This paper reviews the literature on the role of dietary fat in calorie intake and body weight gain in humans and laboratory animals. An overview of 40 animal studies which compared growth on high-fat (HF) and high-carbohydrate (HC) solid/powdered diets indicated that the HF diet elicited greater weight gain in 33 out of 40 studies. Enhanced growth on the HF diet was often, but not exclusively, attributable to greater caloric intake. Additional evidence for the growth-enhancing effect of HF diets emerges from "diet option" and "supermarket" feeding studies in rats, and experimental and epidemiological studies in humans. Three principal factors that contribute to the different responses to HF and HC diets are (a) caloric density, (b) sensory properties and palatability, and (c) postabsorptive processing. It is concluded that both calorie intake and metabolic energy expenditure are biased towards weight gain when a HF diet is consumed, and that the high caloric density of high-fat diets plays a primary role in weight gain. Humans may be biologically predisposed to gain weight when a HF diet is consumed.
The role of dietary fat in the regulation of energy intake was assessed by manipulating a conventional diet and measuring spontaneous food consumption. Twenty-four women each consumed a sequence of three 2-wk dietary treatments in which 15-20%, 30-35%, or 45-50% of the energy was derived from fat. These diets consisted of foods that were similar in appearance and palatability but differed in the amount of high-fat ingredients used. Relative to their energy consumption on the medium-fat diet, the subjects spontaneously consumed an 11.3% deficit on the low-fat diet and a 15.4% surfeit on the high-fat diet (p less than 0.0001), resulting in significant changes in body weight (p less than 0.001). A small amount of caloric compensation did occur (p less than 0.02), which was greatest in the leanest subjects (p less than 0.03). These results suggest that habitual, unrestricted consumption of low-fat diets may be an effective approach to weight control.
Tested the effects of cholecystokinin (CCK) on a total of 120 adult male Sprague-Dawley rats. Partially purified CCK was injected intraperitoneally into fasted Ss prior to food presentation. The hormone produced a large dose-related suppression of intake of solid and liquid diets. Identical doses of the synthetic terminal octapeptide of cholecystokinin produced identical results. An effective dose of CCK did not suppress drinking after water deprivation. Treated Ss did not appear ill and were not hyperthermic; neither CCK nor the octapeptide produced learning of a taste aversion in bait-shyness tests. The effect of CCK is not a property of all gut hormones, since injections of secretin did not affect feeding. These studies raise the possibility that CCK plays an inhibitory role in the short-term control of feeding behavior. (25 ref.)
In comparison with a saline infusion, the infusion of the C-terminal octapeptide of cholecystokinin (4 ng/kg/min) decreased food intake by an average of 122 g in a group of 12 lean men without objective evidence of untoward side effects. Shapes of the cumulative intake curves under the two conditions were similar, but subjects ate less and stopped eating sooner when receiving octapeptide than when receiving saline. These results are consistent with the hypothesis that cholecystokinin is an endogenous signal for postprandial satiety. The results offer promise for the possible use of the octapeptide as an appetite suppressant.
The temporal distribution of food intake and of the two parameters, meal size and meal frequency, was determined in rats exposed to light-dark (LD) cycles and to constant illumination (LL). All three measures displayed characteristic multimodal circadian patterns that entrained to the LD cycle and free-ran in LL. Under both conditions, the circadian rhythm of meal size showed a small phase lag relative to the meal frequency rhythm. Lighting condition had no effect on total daily food intake, or on mean meal size and frequency. However, exposure to LL resulted in an attenuation of the rhythms, accompanied by an increase in postprandial correlations. The results indicate that circadian rhythms of food intake are attributable to circadian oscillations in both meal parameters, and suggest a competitive relationship between circadian rhythms and the metabolic controls underlying the rat's meal pattern.
The results of neural tracing studies suggest that vagal afferent fibers in cervical and thoracic branches innervate the esophagus, lower airways, heart, aorta, and possibly the thymus, and via abdominal branches the entire gastrointestinal tract, liver, portal vein, billiary system, pancreas, but not the spleen. In addition, vagal afferents innervate numerous thoracic and abdominal paraganglia associated with the vagus nerves. Specific terminal structures such as flower basket terminals, intraganglionic laminar endings and intramuscular arrays have been identified in the various organs and organ compartments, suggesting functional specializations. Electrophysiological recording studies have identified mechano- and chemo-receptors, as well as temperature- and osmo-sensors. In the rat and several other species, mostly polymodal units, while in the cat more specialized units have been reported. Few details of the peripheral transduction cascades and the transmitters for signal propagation in the CNS are known. Glutamate and its various receptors are likely to play an important role at the level of primary afferent signaling to the solitary nucleus. The vagal afferent system is thus in an excellent position to detect immune-related events in the periphery and generate appropriate autonomic, endocrine, and behavioral responses via central reflex pathways. There is also good evidence for a role of vagal afferents in nociception, as manifested by affective-emotional responses such as increased blood pressure and tachycardia, typically associated with the perception of pain, and mediated via central reflex pathways involving the amygdala and other parts of the limbic system. The massive central projections are likely to be responsible for the antiepileptic properties of afferent vagal stimulation in humans. Furthermore, these functions are in line with a general defensive character ascribed to the vagal afferent, paraventricular system in lower vertebrates.
In the present study, we tested the hypothesis that a single daily injection of the gut peptide CCK, together with continuous leptin infusion, would produce significantly greater loss of body weight than leptin alone. We found that a single daily intraperitoneal injection of CCK-8 (0.5 microg/kg) significantly enhanced the weight-reducing effects of 0.5 microg/day leptin infused continuously into the lateral ventricle of male Sprague-Dawley rats by osmotic minipump. However, CCK and leptin together did not enhance reduction of daily chow intake. Furthermore, there was no synergistic reduction of 30-min sucrose intake, although a significant main effect of both leptin and CCK was observed on sucrose intake. These results 1) confirm our previous reports of synergy between leptin and CCK on body weight, 2) demonstrate that enhancement of leptin-induced weight loss does not require bolus administration of leptin, and 3) suggest that enhanced body weight loss following leptin and CCK does not require synergistic reduction of food intake by leptin and CCK.
Both inhibitory (satiety) and stimulatory (orexigenic) factors from the gastrointestinal tract regulate food intake. In the case of the satiety hormone cholecystokinin (CCK), these effects are mediated via vagal afferent neurons. We now report that vagal afferent neurons expressing the CCK-1 receptor also express cannabinoid CB1 receptors. Retrograde tracing established that these neurons project to the stomach and duodenum. The expression of CB1 receptors determined by RT-PCR, immunohistochemistry and in situ hybridization in rat nodose ganglia was increased by withdrawal of food for > or =12 hr. After refeeding of fasted rats there was a rapid loss of CB1 receptor expression identified by immunohistochemistry and in situ hybridization. These effects were blocked by administration of the CCK-1 receptor antagonist lorglumide and mimicked by administration of CCK to fasted rats. Because CCK is a satiety factor that acts via the vagus nerve and CB1 agonists stimulate food intake, the data suggest a new mechanism modulating the effect on food intake of satiety signals from the gastrointestinal tract.
Although cholecystokinin A (CCK-A) receptors (CCK-AR) mediate the feeding inhibitory actions of CCK in both rats and mice, the absence of CCK-AR results in species-specific phenotypes. The lack of CCK-AR in Otsuka Long-Evans Tokushima fatty (OLETF) rats results in hyperphagia and obesity. We have suggested that demonstrated increases in meal size and elevated levels of dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) gene expression may contribute to this phenotype. In contrast to OLETF rats, CCK-AR(-/-) mice have normal total daily food intake and do not develop obesity. To assess the basis underlying the different phenotypes in rats and mice lacking CCK-AR, we characterized meal patterns in CCK-AR(-/-) mice and determined whether CCK-AR(-/-) mice exhibited an alteration in DMH NPY gene expression. We demonstrate that although CCK-AR(-/-) mice show a similar dysregulation in meal size as OLETF rats, they do not have an elevation in DMH NPY mRNA expression levels. In fact, intact mice have no CCK-AR in the DMH. Furthermore, in intact rats, NPY and CCK-AR are colocalized in DMH neurons, and parenchymal injection of CCK into the DMH reduces food intake and down-regulates DMH NPY mRNA expression. These results suggest that although CCK-AR plays a role in the mediation of CCK actions in the control of meal size in both rats and mice, CCK-AR seems to contribute to modulating DMH NPY levels only in rats. The deficit in CCK's action in the control of DMH NPY gene expression may play a major role in the obese phenotype in OLETF rats.
This review's objective is to give a critical summary of studies that focused on physiologic measures relating to subjectively rated appetite, actual food intake, or both. Biomarkers of satiation and satiety may be used as a tool for assessing the satiating efficiency of foods and for understanding the regulation of food intake and energy balance. We made a distinction between biomarkers of satiation or meal termination and those of meal initiation related to satiety and between markers in the brain [central nervous system (CNS)] and those related to signals from the periphery to the CNS. Various studies showed that physicochemical measures related to stomach distension and blood concentrations of cholecystokinin and glucagon-like peptide 1 are peripheral biomarkers associated with meal termination. CNS biomarkers related to meal termination identified by functional magnetic resonance imaging and positron emission tomography are indicators of neural activity related to sensory-specific satiety. These measures cannot yet serve as a tool for assessing the satiating effect of foods, because they are not yet feasible. CNS biomarkers related to satiety are not yet specific enough to serve as biomarkers, although they can distinguish between extreme hunger and fullness. Three currently available biomarkers for satiety are decreases in blood glucose in the short term (<5 min), which have been shown to be involved in meal initiation; leptin changes during longer-term (>2-4 d) negative energy balance; and ghrelin concentrations, which have been implicated in both short-term and long-term energy balance. The next challenge in this research area is to identify food ingredients that have an effect on biomarkers of satiation, satiety, or both. These ingredients may help consumers to maintain their energy intake at a level consistent with a healthy body weight.
CCK and ghrelin exert antagonistic effects on ingestive behavior. The aim of the present study was to investigate the interaction between ghrelin and CCK administered peripherally on food intake and neuronal activity in specific hypothalamic and brain stem nuclei, as assessed by c-Fos-like immunoreactivity (c-FLI) in nonfasted rats. Ghrelin (13 microg/kg body wt) injected intraperitoneally significantly increased the cumulative food intake when measured at 30 min and 1 h after injection, compared with the vehicle group (2.9 +/- 1.0 g/kg body wt vs. 1.2 +/- 0.5 g/kg body wt, P < 0.028). Sulfated CCK octapeptide (CCK-8S) (2 or 25 microg/kg body wt) injected simultaneously blocked the orexigenic effect of ghrelin (0.22 +/- 0.13 g/kg body wt, P < 0.001 and 0.33 +/- 0.23 g/kg body wt, P < 0.0008), while injected alone, both doses of CCK-8S exerted a nonsignificant trend to reduce food intake. Ghrelin (13 microg/kg body wt ip) markedly increased the number of c-FLI-positive neurons per section in the arcuate nucleus (ARC) compared with vehicle (median: 31.35 vs. 9.86, P < 0.0001). CCK-8S (2 or 25 microg/kg body wt ip) had no effect on neuronal activity in the ARC, as assessed by c-FLI (median: 5.33 and 11.21 cells per section), but blocked the ghrelin-induced increase of c-fos expression in this area when both peptides were administered simultaneously (median: 13.33 and 12.86 cells per section, respectively). Ghrelin at this dose had no effect on CCK-induced stimulation of c-fos expression in the paraventricular nucleus of the hypothalamus and the nucleus of the solitary tract. These results suggest that CCK abolishes ghrelin-induced food intake through dampening increased ARC neuronal activity.
Intact vagal afferent neurons are required for the satiety effects of the intestinal hormone cholecystokinin (CCK) and the orexigenic effects of the gastric regulatory peptide ghrelin. In this study, we examined the localization of ghrelin receptors in nodose ganglia and their function in regulating the expression of other orexigenic receptors, notably cannabinoid (CB)-1 and melanin-concentrating hormone (MCH)-1 receptors. With the use of RT-PCR, transcripts corresponding to both functional [growth hormone secretagogue receptor (GHS-R)1a] and truncated forms (GHS-R1b) of the ghrelin receptor were detected in rat nodose ganglia. There was no difference in expression between rats fed ad libitum or fasted for up to 48 h. Immunohistochemical studies using antibodies directed at GHS-R1a revealed expression in over 75% of neurons also expressing CCK-1 receptors in the mid- and caudal regions of the ganglion. There was also expression in human nodose ganglia. In fasted rats in which CB-1 and MCH-1 receptor expression was increased, administration of ghrelin prevented the downregulation by refeeding. We conclude that the actions of CCK and ghrelin are mediated by a common population of vagal afferent neurons. Ghrelin may act to limit the action of CCK in depressing expression of CB-1 and MCH-1 receptors and other receptors.
The brain-gut peptide cholecystokinin (CCK) inhibits food intake following peripheral or site directed central administration. Peripheral exogenous CCK inhibits food intake by reducing the size and duration of a meal. Antagonist studies have demonstrated that the actions of the exogenous peptide mimic those of endogenous CCK. Antagonist administration results in increased meal size and meal duration. The feeding inhibitory actions of CCK are mediated through interactions with CCK-1 receptors. The recent identification of the Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat as a spontaneous CCK-1 receptor knockout model has allowed a more comprehensive evaluation of the feeding actions of CCK. OLETF rats become obese and develop non-insulin dependent diabetes mellitus (NIDDM). Consistent with the absence of CCK-1 receptors, OLETF rats do not respond to exogenous CCK. OLETF rats are hyperphagic and their increased food intake is characterized by a large increase in meal size with a decrease in meal frequency that is not sufficient to compensate for the meal size increase. Deficits in meal size control are evident in OLETF rats as young as 2 days of age. OLETF obesity is secondary to the increased food intake. Pair feeding to amounts consumed by intact control rats normalizes body weight, body fat and elevated insulin and glucose levels. Hypothalamic arcuate nucleus peptide mRNA expression in OLETF rats is appropriate to their obesity and is normalized by pair feeding. In contrast, pair fed and young pre-obese OLETF rats have greatly elevated dorsomedial hypothalamic (DMH) neuropeptide Y (NPY) mRNA expression. Elevated DMH NPY in OLETF rats appears to be a consequence of the absence of CCK-1 receptors. In intact rats NPY and CCK-1 receptors colocalize to neurons within the compact subregion of the DMH and local CCK administration reduces food intake and decreases DMH NPY mRNA expression. We have proposed that the absence of DMH CCK-1 receptors significantly contributes to the OLETF's inability to compensate for their meal size control deficit leading to their overall hyperphagia. Access to a running wheel and the resulting exercise normalizes food intake and body weight in OLETF rats. When given access to running wheels for 6 weeks shortly after weaning, OLETF rats do not gain weight to the same degree as sedentary OLETF rats and do not develop NIDDM. Exercise also prevents elevated levels of DMH NPY mRNA expression, suggesting that exercise exerts an alternative, non-CCK mediated, control on DMH NPY. The OLETF rat is a valuable model for characterizing actions of CCK in energy balance and has provided novel insights into interactions between exercise and food intake.
In comparison with a saline infusion, the infusion of the C-terminal octapeptide of cholecystokinin (4 ng/kg/min) decreased food intake by an average of 122 g in a group of 12 lean men without objective evidence of untoward side effects. Shapes of the cumulative intake curves under the two conditions were similar, but subjects ate less and stopped eating sooner when receiving octapeptide than when receiving saline. These results are consistent with the hypothesis that cholecystokinin is an endogenous signal for postprandial satiety. The results offer promise for the possible use of the octapeptide as an appetite suppressant.
Size of meals taken by normal rats was greatly increased by following each spontaneously initiated meal with gastric infusion of additional diet. In a second experiment, rats in the dynamic phase of hypothalamic obesity were limited to meals much smaller than the unusually large ones they usually take. In both experiments rats made precise adjustments in meal frequency which maintained daily food intakes at or close to pre-experimental levels.
To test the possibility that endogenous cholecystokinin (CCK) participates in suppression of sham feeding by intraintestinal nutrient infusions, we examined the effect of CCK-receptor antagonists on the suppression of sham feeding by intraintestinally infused oleic acid, maltose or L-phenylalanine (L-Phe). In addition, we monitored amylase activity in the intestinal lumen during some sham feeding experiments and measured plasma CCK in parallel experiments using intestinally infused animals that were not feeding. Suppression of sham feeding by oleic acid or maltose was attenuated by CCK-receptor antagonists, while suppression of sham feeding by L-Phe was not. Oleate infusion increased plasma CCK concentration and luminal amylase activity. Oleate-induced increase in luminal amylase activity was attenuated by a CCK-receptor antagonist. Intraintestinal maltose or L-Phe did not increase plasma CCK concentration or luminal amylase activity, suggesting that they did not release endocrine CCK. These results suggest 1) that endogenous CCK mediates suppression of sham feeding by oleate and maltose but not by L-Phe and 2) that CCK participating in suppression of feeding by intestinal stimuli might not be of endocrine origin.
To test the hypothesis that endogenous cholecystokinin (CCK) released from the small intestine by ingested food produces a satiating effect by acting at CCKA-receptors, we measured the effect of slow continuous intravenous infusions of three doses of MK-329, a potent and selective CCKA-antagonist, on food intake during 2.5-h tests in 13 Sprague-Dawley male rats after 1 h of food deprivation. MK-329 increased food intake significantly and the lowest dose tested (0.5 mg.kg-1.h-1) produced the most consistent effect on cumulative intake. Part of the increased food intake under these conditions was due to a decrease in the satiating effect of food ingested at the first meal on the postprandial intermeal interval. These results are consistent with, but do not prove, the hypothesis that the satiating effect of endogenous CCK released from the small intestine by ingested food is mediated by CCKA-receptors.
The cholecystokinin (CCK) receptor antagonist L 364718 was used to examine the role of CCK in control of food intake. Effects of L 364718 (0.01-1 mg/kg ip) on the feeding response to a maximal inhibitory dose of cholecystokinin COOH-terminal octapeptide (CCK-8; 8 nmol/kg ip) and on food intake alone were determined in rats fed ad libitum during the dark cycle. CCK-8 suppressed feeding by 48%. L 364718 reversed this effect dose dependently; the minimal effective dose was 0.03 mg/kg, and complete reversal occurred at 0.1 and 0.3 mg/kg. L 364718 (0.03 mg/kg) caused a parallel, rightward shift in the dose-response curve to CCK-8 [1-128 nmol/kg, half-maximal effective dose (ED50) increased 16-fold] but did not alter the maximal response, consistent with competitive-like kinetics. L 364718 stimulated liquid and solid food intake dose-dependently by 11-35%. The minimal effective dose was 0.1 mg/kg; maximal stimulation occurred at 0.3 mg/kg. Duodenal infusion of bile-pancreatic juice did not alter the response. These results support an important role for CCK in control of food intake.
A sensitive and specific bioassay for the measurement of cholecystokinin (CCK) in human plasma was developed to determine the molecular forms of CCK in circulation, CCK responses to feeding, and the physiologic role of CCK in gallbladder contraction. First, plasma was quantitatively extracted and concentrated with octadecylsilylsilica, and the extracts were then assayed for their ability to stimulate amylase release from isolated rat pancreatic acini. Acini were highly sensitive to CCK whereas gastrin reacted only weakly in this system. With the assay, plasma levels of cholecystokinin octapeptide (CCK-8) bioactivity as low as 0.2 pM were detectable. CCK bioactivity in plasma was inhibited by the CCK antagonist, bibutyryl cyclic guanosine monophosphate, and was eliminated by immunoadsorption with an antibody directed against the carboxyl terminus of CCK. Detection of fasting levels of CCK was possible in all individuals tested and averaged 1.0 +/- 0.2 pM (mean +/- SE, n = 22) CCK-8 equivalents. Plasma CCK biological activity was normal in patients with gastrin-secreting tumors. After being fed a mixed liquid meal, CCK levels rose within 15 min to 6.0 +/- 1.6 pM. The individual food components fat, protein, and amino acids were all potent stimulants of CCK secretion; in contrast, glucose caused a significant but smaller elevation in plasma CCK levels. Gel filtration studies identified three major forms of CCK bioactivity in human plasma: an abundant form that eluted with CCK-33, a smaller form that eluted with CCK-8, and an intermediate form that eluted between CCK-33 and CCK-8. Ultrasonic measurements of gallbladder volume indicated that this organ decreased 51% in size 30 min after feeding a mixed liquid meal. This contraction occurred coincidentally with the increase in plasma CCK levels. Next CCK-8 was infused to obtain CCK levels similar to postprandial levels. This infusion caused a decrease in gallbladder volume, similar to that seen with a meal. The present studies indicate, therefore, that CCK can be bioassayed in fasting and postprandial human plasma. These studies also suggest that CCK may be an important regulator of gallbladder contraction.
Food intake of four adult male baboons (Papio c. anubis) was monitored during daily experimental sessions lasting 22h. Food was available under a two-component operant schedule. Following completion of the first "procurement component" response requirement, access to food, i.e. a meal, became available under the second "consumption component" during which each response produced a 1-g food pellet. After a 10-min interval in which no response occurred, the consumption component was terminated. A long-acting cholecystokinin (CCK) analog U-67827E (U-67: 0.80-3.2 micrograms/kg) was administered, in the thigh muscle, at 1100 hrs immediately prior to the start of the daily session on Tuesdays and Fridays. U-67 significantly reduced intake during the first 8-h of the session, and intake during the entire 22-h session. The decreased intake was due to a significant decrease in the size of the first meal of the session as a consequence of decreased duration of feeding without a change in response rate. U-67 also produced dose-dependent increases in latency to the first meal of up to 2.5 h. These results demonstrate that a long-acting CCK analog decreases food intake over a prolonged period of time in a naturalistic feeding situation. In addition, the effects of U-67 were limited to the consumption component, suggesting that this CCK analog affected food intake by interacting with physiological mechanisms specifically associated with feeding.
Rats in a laboratory foraging paradigm were offered each of four diets which differed in caloric density, and intakes, meal frequencies, meal sizes, and eating rates were monitored. The rats maintained a constant daily caloric intake by eating more frequent, larger meals of the lower density foods. However, caloric meal size was not regulated, and significant correlations between meal size and the length of the post-meal interval were rarely found. The 24-hour pattern of calorie intake was the same regardless of diet. Higher-calorie foods were consumed at a faster rate within meals than were lower-calorie foods. The feeding patterns observed suggest that caloric intake may be regulated over a time frame of several meals rather than on a meal-to-meal basis.
Because of prior difficulties in measuring plasma cholecystokinin (CCK) levels, it has not been established which components of food stimulate CCK secretion in rats. In the present study, we used a sensitive and specific bioassay for measuring plasma CCK and determined the effects of proteins, protein hydrolysates, amino acids, fats, starch, and glucose on CCK secretion in this species. Intact proteins were the only stimulants of CCK release. Solutions of 18% casein and 0.2% soybean trypsin inhibitor caused prompt increases in plasma CCK levels from 0.5 +/- 0.2 to 7.9 +/- 1.9 and 8.0 +/- 2.0 pM, respectively, within 5 min of orogastric administration. The proteins lactalbumin and bovine serum albumin caused smaller elevations in circulating CCK. In contrast, hydrolysates of casein and lactalbumin and the amino acids L-phenylalanine and L-tryptophan did not stimulate CCK release. In addition, plasma CCK levels did not increase with the feeding of fat, starch, or glucose. The ability of proteins to stimulate CCK secretion paralleled their ability to inhibit trypsin activity in vitro. Furthermore, the plasma CCK response to casein was completely abolished by the simultaneous administration of trypsin. These studies indicate that proteins are the major food stimulants of CCK release in the rat and that the effects of proteins are related to inhibition of intraluminal protease activity.
These experiments demonstrate that rats can immediately adjust their meal size in response to variations in the caloric density of a novel diet. However, this immediate caloric sensitivity only seems to appear when rats have been adapted to small, calorically insufficient meals. Rats in Experiment 1 were given timed access to unlimited quantities of an oil/water diet during baseline, and they showed no indication of compensating for changes in the caloric density of the oil/water diet during a test meal. Instead, they consumed about the same amount they had consumed during the preceding baseline meal, suggesting that a learned habit of consuming a certain volume of food controlled their meal size. In contrast, rats that were accustomed to receiving only a very small quantity of food for one of their daily meals during baseline immediately responded to the caloric density of an oil/water test diet by consuming a larger meal if the diet was dilute than if it was calorically more concentrated (Experiments 2 and 3). This immediate sensitivity to caloric density occurred whether or not the rats were exposed to the oil/water diet during baseline, suggesting that rats have some way of directly "metering" the caloric density of new foods. Thus, rats' caloric intake during a meal appears to be controlled by two factors: under certain conditions, control is by caloric learning, under other conditions control is by a caloric metering mechanism.
Six of eight obese men ate significantly less food during an intravenous infusion of the C-terminal octapeptide of cholecystokinin (CCK-8, 4 ng . kg-1 . min-1) than during a saline infusion in a double blind experimental paradigm. Subjects stopped eating sooner during CCK-8. CCK-8 did not change the rate of eating. No overt side effects were reported or observed. This is the first report of the satiety effect of CCK-8 in obese humans and it suggests that the therapeutic potential of CCK-8 for the treatment of obesity deserves investigation.
Food and water intake of free-feeding rats with indwelling intraperitoneal catheters connected to infusion pumps was continuously monitored and recorded by a microcomputer-based data acquisition system. Initially, at the start of every spontaneous meal for 4 days, each rat was infused with 0.27 ml of physiological saline. Saline infusion did not affect any feeding or drinking patterns, and the rate of weight gain remained unchanged. For 6 subsequent days, the octapeptide of cholecystokinin (CCK-8, 1.1 micrograms/meal) dissolved in physiological saline was infused at the onset of each meal. CCK-8 infusion caused a dramatic shift of patterns of food intake. Average meal size was reduced by at least 44%, whereas daily meal number increased by 162% or more for all 6 days of CCK-8 infusion. Total daily food intake recovered to predrug levels by the 4th day of CCK-8 infusion, primarily due to increased feeding frequency. Average body weight dropped by 12.4 g on the 1st day of CCK infusion, but over the following 5 days the growth rate was not different from the base-line predrug rate. With discontinuation of CCK-8 infusion all meal patterns returned rapidly to normal and body weight immediately recovered.
Cholecystokinin (CCK, 20% pure) inhibited liquid food intake in obese and lean male mice after 1.5 and 4.5 hr of food deprivation. CCK decreased meal size without changing the duration of the postprandial intermeal interval. The inhibition of food intake was relatively specific. The largest dose of CCK tested (40 U/kg) had no effect on water intake in lean mice and it merely changed the pattern of intake in obese mice. Obese mice were as sensitive as lean mice to the satiating effect of CCK after 1.5 hr and 4.5 hr of food deprivation. Since CCK decreased meal size in obese mice and since obese mice were normally sensitive to CCK, CCK could be the circulating satiety factor that Coleman [4] postulated was deficient in obese mice. The results, however, only indicate that CCK could be the deficient factor. Other experiments are required to prove the point.
Foraging involves the expenditure of both time and effort in the acquisition of food; animals typically modify their meal patterns so as to reduce these expenditures or costs. The contribution of time, as compared with effort, to the overall cost perceived by an animal is not known. We investigated the effect of foraging time as a cost independent of effort by measuring the meal patterns of rats living in a laboratory foraging simulation in which they earned all their daily intake. They pressed a bar once to initiate an interval (procurement interval) leading to the presentation of a large cup of food from which they could eat a meal of any size. As the length of the interval increased from 1 s to 46 hr, meal frequency decreased regularly. Meal size increased in a compensatory fashion, and total daily intake was conserved through an interval of 23 hr. The changes in meal frequency occurred because of changes in the rat's latency to bar press after each meal. The functions relating meal frequency and size to the procurement interval were of the same shape as those seen when cost is the completion of a bar-press requirement, which entails the expenditure of both effort and time. When the bar-press requirement was increased to 10, meal frequency was reduced, but time and effort did not appear to simply add together in the rat's perception of cost. These data reveal that time is preceived to be a cost by rats foraging in this laboratory environment. These results suggest that the time parameters of foraging are different from those of consumption.
The genetically obese Zucker rat (fa/fa) is hyperphagic compared to lean controls (Fa/?). This hyperphagia is characterized by increased meal size. Cholecystokinin (CCK) has been shown to decrease meal size in many species including humans. In the present study we investigated the role of endogenous CCK in mediating the hyperphagia of male and female obese Zucker rats. CCKA-type receptors were blocked with the specific antagonist, devazepide, and test meal size was measured. Male obese and lean rats significantly increased food intake following devazepide. Neither obese nor lean female rats significantly increased food intake following devazepide. This is the first demonstration of a gender difference in endogenous CCK-mediated satiety. These results have implications for the higher incidence of eating disorders in females.
To assess the role of subdiaphragmatic vagal afferent and efferent fibers in the mediation of the inhibition of food intake by cholecystokinin (CCK), we compared the ability of a dose range (1-16 microg/kg), of CCK to affect 30-min liquid glucose (0.125 g/ml) intake in rats with either total subdiaphragmatic vagotomy, selective subdiaphragmatic vagal deafferentation, selective subdiaphragmatic vagal deefferentation, or sham surgery. Selective vagal deafferentation and deefferentations were produced by combinations of unilateral subdiaphragmatic vagotomy and contralateral afferent or efferent rootlet transection as fibers enter the caudal medulla. CCK produced a dose-related suppression of glucose intake in sham animals, and this action was eliminated in rats with total subdiaphragmatic vagotomy. CCK suppression of intake was attenuated in rats with vagal deafferentation, such that there was a loss of sensitivity to CCK. Vagal deefferentation resulted in lower levels of baseline intake and a truncation of the feeding-inhibitory actions of CCK. These data demonstrate that CCK's suppression of intake depends on actions of both vagal afferent and efferent fibers. We interpret these data as suggesting that 1) the actions of low doses of CCK depend on activation of vagal afferent CCK receptors and 2) the greater efficacy of higher CCK doses is the result of the potentiation of these vagal afferent actions due to local physiological gastrointestinal effects of the peptide that rely on vagal efferent input.
Partially purified cholecystokinin (CCK) was injected intraperitoneally into fasted rats prior to food presentation. The hormone produced a large doserelated suppression of intake of solid and liquid diets. Identical doses of the synthetic terminal octapeptide of cholecystokinin produced identical results. An effective dose of CCK did not suppress drinking after water deprivation. Treated animals did not appear ill and were not hyperthermic; neither CCK nor the octapeptide produced learning of a taste aversion in bait-shyness tests. The effect of CCK is not a property of all gut hormones, since injections of secretin did not affect feeding. These studies raise the possibility that CCK plays an inhibitory role in the short-term control of feeding behavior.
The present study explored the effects of intravenous gastrin-releasing peptide1-27 (GRP) on the postprandial intermeal interval (IMI) when delivered shortly after termination of the first spontaneous nocturnal meal in freely-feeding rats. Undisturbed, ad lib-fed (milk), male rats (n = 11) with chronic inferior vena caval catheters were infused with saline and each of three doses (2.5, 5 and 10 nmol/kg) of GRP in counterbalanced order. Infusions began 5 min after the last lick of the first nocturnal meal and continued for 2 min (60 microliters/min), with delivery of the peptide during the first minute. Infusions and recording of meal data (licks) were fully automated and computer-controlled. Both 5 and 10 nmol/kg of GRP significantly prolonged the IMI by over 50%, but had no effect on the size of the following meal. This is the first demonstration of the prolongation of the IMI by intravenous GRP in undisturbed, freely-feeding rats, and the result suggests that endogenous GRP may play a role in the control of the postprandial intermeal interval.
The present study has investigated whether fatty acids directly influence peptide release from enteroendocrine cells using STC‐1, a mouse intestinal endocrine tumour cell line, previously shown to release cholecystokinin (CCK) in response to other physiological stimuli.
Fatty acids elicited a chain length‐ and dose‐dependent stimulation of CCK secretion. Dodecanoic acid (C12) was most effective, producing up to a 5‐fold increase in CCK secretion. Fatty acids with less than ten carbon atoms did not increase secretion. The chain length dependence of these effects mimics closely fatty acid‐induced CCK secretion previously observed in humans in vivo.
Esterification of C12 abolished CCK secretion, indicating a critical role for a free carboxyl group in eliciting secretion. In contrast, modification of the methyl terminus had no effect on C12‐induced secretion. The non‐metabolizable C12 analogue 2‐bromododecanoic acid was equally effective.
C12 elicited a marked increase in intracellular calcium levels (200–300 n m ) in STC‐1 cells which was abolished by the L‐type Ca ²⁺ channel antagonist nicardipine. In contrast, C8 produced a smaller and more transient Ca ²⁺ response. C12‐induced CCK secretion was also blocked by nicardipine.
These data suggest that fatty acids can interact directly with enteroendocrine cells to stimulate CCK secretion via increases in intracellular calcium mediated primarily by L‐type Ca ²⁺ channels.
Intraduodenal fat inhibits gastric emptying and exerts early satiation in animals and humans, but it is not clear whether the effects are mediated by cholecystokinin (CCK) in humans. Here, we tested whether CCK-A receptors mediate the inhibition of fat on food intake. Two sequential, double-blind, crossover studies were performed in 24 male subjects. First, subjects received either intraduodenal fat or saline together with a preload of either water or banana shake. Second, 12 subjects received either intraduodenal fat or saline perfusion plus a concomitant infusion of saline or loxiglumide, a specific CCK-A receptor antagonist, together with a preload of banana shake. In both studies, subjects were free to eat and drink as much as they wished. Fat induced a reduction in calorie intake (P < 0.05) compared with controls. Furthermore, a decrease in hunger feelings was observed. Infusion of loxiglumide abolished the effects of fat. Duodenal fat interacts with an appetizer to modulate energy intake in humans. This effect is mediated by CCK-A receptors.
Previously, rats fed a high-fat liquid diet (HF) ad libitum consumed more kilocalories and had greater weight gain than rats fed a liquid high-carbohydrate diet (HC) of equivalent energy density (Warwick, Z. S., and H. P. Weingarten. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 269: R30-R37, 1995). The present series of experiments sought to clarify the behavioral expression of HF hyperphagia by comparing HF and HC with regard to meal size and magnitude of postingestive satiety effect. Meal size of HF was greater than HC at 2.3 kcal/ml and also when diets were formulated at 1.15 kcal/ml. In a preload-test meal paradigm, an orally consumed HF preload was less satiating than a calorically equivalent HC preload across a range of preload volumes and intermeal intervals. Sensory-specific satiety was ruled out as an explanation of the relatively greater intake of test meal after an HF preload meal; an intragastrically delivered HF preload was less satiating than intragastric HC. Furthermore, a fat (corn oil emulsion) preload was less satiating than a carbohydrate (sucrose) preload when an evaporated milk test meal was used. These findings indicate that hyperphagia on an HF diet is expressed in increased meal size and decreased intermeal interval.
Studies of meal patterning have made an important contribution to our understanding of ingestive behaviour. This paper initially reviews studies of normal meal patterning in rodents, with an emphasis on the determination of suitable meal criteria. Studies of serotonergic mechanisms in the control of meal size and feeding rate suggest important roles for the 5HT1B and 5-HT2C receptor. Analysis of dopaminergic mechanisms show that dopamine D2 receptor blockade is associated with enhancement of meal size and decrease of meal frequency; this probably represents a failure to switch from feeding to other behaviour when a meal is expected to terminate. Finally studies are described demonstrating that lesions of several forebrain structures, including hippocampus and nucleus accumbens, lead to a similar syndrome of short, frequent meals with little evidence of a deficit in body weight regulation. These structures may play a role in the organisation of meal patterning.
It has been recognized for some time that a number of different neuropeptides exert powerful effects on food intake. During the last few years, the neurocircuitry within which these peptides operate has also begun to be elucidated. Peptidergic feeding-regulatory neurones are found both in the hypothalamus and the brainstem, where they act as input stations for hormonal and gastrointestinal information, respectively. These cell populations both project to several other brain regions and interconnect extensively. The present review summarizes the neuroanatomy and connectivity of some prominent peptides involved in food intake control, including neuropeptide Y, melanocortin peptides, agouti gene-related protein, cocaine- and amphetamine-regulated transcript, orexin/hypocretin, melanin-concentrating hormone and cholecystokinin. Disturbances in the hypothalamic neuropeptide systems have been implicated in the phenotype of a genetic model of fatal hypophagia, the mouse anorexia (anx) mutation, which is also discussed.
Neurotrophin-4 (NT-4) knockout mice exhibited decreased innervation of the small intestine by vagal intraganglionic laminar endings (IGLEs) and reduced food satiation. Recent findings suggested this innervation was increased in NT-4 knock-in (NT-4KI) mice. Therefore, to further investigate the relationship between intestinal IGLEs and satiation, meal patterns were characterized using solid and liquid diets, and cholecystokinin (CCK) effects on 30-min solid diet intake were examined in NT-4KI and wild-type mice. NT-4KI mice consuming the solid diet exhibited reduced meal size, suggesting increased satiation. However, compensation occurred through increased meal frequency, maintaining daily food intake and body weight gain similar to controls. Mutants fed the liquid diet displayed a decrease in intake rate, again implying increased satiation, but meal duration increased, which led to an increase in meal size. This was compensated for by decreased meal frequency, resulting in similar daily food intake and weight gain as controls. Importantly, these alterations in NT-4KI mice were opposite, or different, from those of NT-4 knockout mice, further supporting the hypothesis that they are specific to vagal afferent signaling. CCK suppressed short-term intake in mutants and controls, but the mutants exhibited larger suppressions at lower doses, implying they were more sensitive to CCK. Moreover, devazepide prevented this suppression, indicating this increased sensitivity was mediated by CCK-1 receptors. These results suggest that the NT-4 gene knock-in, probably involving increased intestinal IGLE innervation, altered short-term feeding, in particular by enhancing satiation and sensitivity to CCK, whereas long-term control of daily intake and body weight was unaffected.
Mice, with the variety of genotypes they provide, should be particularly useful for studies of growth factors and gene products in regeneration of autonomic pathways such as the vagus nerve. To provide a foundation for examinations of mouse vagal reorganization, two experiments assessed the rate, extent, and accuracy of afferent reinnervation of the stomach after vagotomy and related these patterns to feeding behavior. In experiment 1, the pattern of afferent regrowth into the gut after unilateral truncal vagotomy was characterized by labeling of these afferents with wheat germ agglutinin-horseradish peroxidase and Micro-Ruby. Regenerating neurites had reached and, in some cases, already reinnervated the stomach by 4 wk after axotomy. By 8 wk, regrowth was more extensive, and many fibers had redifferentiated terminals in the smooth muscle. By 16 wk, vagal projections had reached or exceeded normal density in the corpus, density in the forestomach was still reduced, and regrowth in the antrum was minimal. At all time points, not only appropriate terminals, but also growth cones and aberrant endings, were observed. In experiment 2, meal patterns of vagotomized mice were evaluated using a solid diet over the period of regeneration; cholecystokinin suppression of a liquid meal after unilateral and bilateral truncal vagotomies was also evaluated. Unilaterally, as well as bilaterally, vagotomized animals ate smaller and more frequent meals. These disturbed patterns became more pronounced in the first 8 wk after vagotomy, during regeneration. Cholecystokinin inhibition of intake was attenuated by bilateral, but not unilateral, vagotomy. Overall, the spatial and temporal patterns of structural and functional changes observed during regeneration verify that the mouse provides a useful preparation for examining the control of vagal plasticity.
A series of studies in rat using isoenergetic (kcal/ml) liquid diets differing in fat content has previously found dietary fat to dose-dependently increase daily caloric intake. In single-meal tests in which meal initiation was externally evoked in feeding-associated environments, the behavioral expression of this overeating was found to be larger meal intake. The present studies confirmed the ecological validity of this larger meal size of high-fat diet (HF) relative to high-carbohydrate diet (HC): meal size of HF>HC in home-cage testing (Experiment 1), and during undisturbed, spontaneous feeding in which ingestive behavior was continuously monitored (Experiments 2 and 3). These findings demonstrate that single-meal paradigms yield results consistent with spontaneous feeding of high-fat and high-carbohydrate liquid diets, thus supporting the use of single-meal studies to better understand the physiological bases of elevated caloric intake associated with chronic consumption of a high-fat diet.
Cholecystokinin (CCK), acting at CCK1 receptors (CCK1Rs) on intestinal vagal afferent terminals, has been implicated in the control of gastrointestinal function and food intake. Using CCK1R(-/-) mice, we tested the hypothesis that lipid-induced activation of the vagal afferent pathway and intestinal feedback of gastric function is CCK1R dependent. In anesthetized CCK1R(+/+) ("wild type") mice, meal-stimulated gastric acid secretion was inhibited by intestinal lipid infusion; this was abolished in CCK1R(-/-) mice. Gastric emptying of whole egg, measured by nuclear scintigraphy in awake mice, was significantly faster in CCK1R(-/-) than CCK1R(+/+) mice. Gastric emptying of chow was significantly slowed in response to administration of CCK-8 (22 pmol) in CCK1R(+/+) but not CCK1R(-/-) mice. Activation of the vagal afferent pathway was measured by immunohistochemical localization of Fos protein in the nucleus of the solitary tract (NTS; a region where vagal afferents terminate). CCK-8 (22 pmol ip) increased neuronal Fos expression in the NTS of fasted CCK1R(+/+) mice; CCK-induced Fos expression was reduced by 97% in CCK1R(-/-) compared with CCK1R(+/+) mice. Intralipid (0.2 ml of 20% Intralipid and 0.04 g lipid), but not saline, gavage increased Fos expression in the NTS of fasted CCK1R(+/+) mice; lipid-induced Fos expression was decreased by 47% in CCK1R(-/-) compared with CCK1R(+/+)mice. We conclude that intestinal lipid activates the vagal afferent pathway, decreases gastric acid secretion, and delays gastric emptying via a CCK1R-dependent mechanism. Thus, despite a relatively normal phenotype, intestinal feedback in response to lipid is severely impaired in these mice.
During a meal and after a meal, ingested nutrients alter the release of a variety of gut peptides that have the potential to modulate food intake. Such feedback peptide signaling can be conceptualized as having three outcomes: meal termination, inhibitory modulation of intake in subsequent meals, and orexigenic modulation. Cholecystokinin, pancreatic glucagons, and amylin are examples of peptides involved in meal termination. They are released rapidly with the onset of feeding and have short durations of action. Peptide YY(3-36) and glucagon-like peptide 1 are peptides for which longer-term feeding inhibitory actions have been proposed. They are released from the distal intestine and have longer durations of actions. Ghrelin is a gastric peptide that stimulates food intake after its exogenous administration. Plasma ghrelin levels fall with feeding and rise with food deprivation. All of these gut peptides have vagal or dorsal hindbrain mediation. Their potential as targets for the development of anti-obesity treatments is under study.
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[PubMed: 3714871] Donovan et al. Page 8 Physiol Behav. Author manuscript; available in PMC 2009 April 30. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript