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Neuropeptides and appetite control
Abstract
Obesity is important in the aetiology of type 2 diabetes, and presents a major barrier to its successful prevention and management. Obesity develops when energy intake exceeds energy expenditure over time. A complex system has evolved to maintain energy homeostasis, but this is biased towards weight gain. Meal size is controlled by a series of short-term hormonal and neural signals that derive from the gastrointestinal tract, such as cholecystokinin whereas others may initiate meals, such as the recently discovered hormone, ghrelin. Other hormones such as insulin and leptin, together with circulating nutrients, indicate long-term energy stores. All these signals act at several central nervous system (CNS) sites but the pathways converge on the hypothalamus, which contains a large number of peptide and other neurotransmitters that influence food intake. As energy deficit is most likely to compromise survival, it is not surprising that the most powerful of these pathways are those that increase food intake and decrease energy expenditure when stores are depleted. When energy stores are low, production of leptin from adipose tissue, and thus circulating leptin concentrations fall, leading to increased production of hypothalamic neurotransmitters that strongly increase food intake, such as neuropeptide Y (NPY), galanin and agouti-related protein (AGRP) and decreased levels of alpha-melanocyte-stimulating hormone (alpha-MSH), cocaine and amphetamine-regulated transcript (CART) and neurotensin that reduce food intake and increase energy expenditure. The finding that mutations in leptin and POMC lead to severe early onset obesity in humans has highlighted the importance of these peptides in humans. This new understanding may eventually lead to new treatments for obesity that will be of particular benefit in the prevention and treatment of type 2 diabetes.
... For instance, one neuronal circuit inhibits food intake via the expression of proopiomelanocortin (POMC), and another stimulates food intake through expression of Neuropeptide Y (NPY). [15][16][17][18] Leptin is a peptide hormone secreted by adipose tissue that is transported across the blood brain barrier to activate POMC neurons, thereby inhibiting food intake. 17,18 Conversely, ghrelin is released by the oxyntic cells of the stomach, small-, and large intestine that serves as a hunger signal during fasting by stimulating NPY neurons centrally, thereby increasing food intake. ...
... [15][16][17][18] Leptin is a peptide hormone secreted by adipose tissue that is transported across the blood brain barrier to activate POMC neurons, thereby inhibiting food intake. 17,18 Conversely, ghrelin is released by the oxyntic cells of the stomach, small-, and large intestine that serves as a hunger signal during fasting by stimulating NPY neurons centrally, thereby increasing food intake. 17,18 Peptide tyrosine-tyrosine (Peptide YY, PYY) is released mainly from the gastrointestinal tract in response to feeding and acts as an agonist of the Y2 receptor in the hypothalamus. ...
... 17,18 Conversely, ghrelin is released by the oxyntic cells of the stomach, small-, and large intestine that serves as a hunger signal during fasting by stimulating NPY neurons centrally, thereby increasing food intake. 17,18 Peptide tyrosine-tyrosine (Peptide YY, PYY) is released mainly from the gastrointestinal tract in response to feeding and acts as an agonist of the Y2 receptor in the hypothalamus. When activated, the Y2 receptor inhibits the release of NPY and suppresses appetite. ...
Background: Insulin detemir is long-acting insulin analog that is weight-neutral compared with other long-acting insulins in patients with type 1 diabetes. One mechanism for this may be an effect of insulin detemir to enhance satiety. We hypothesized that type 1 diabetes patients on insulin detemir will eat fewer calories when presented with a standardized buffet meal following a 24-hour fast as compared to those on insulin glargine. Methods: Ten subjects with C-peptide negative type 1 diabetes participated in a randomized, double-blind crossover study in which they received equivalent doses of either insulin detemir or insulin glargine twice daily for at least 3 weeks. They were subsequently admitted to the UNM Clinical Research Unit for a 24-hour fast, after which they were allowed to eat to satiety from a standardized buffet. Caloric consumption, hunger score and body compositions were measured. Leptin, Ghrelin and Peptide YY were assessed at baseline, after 24-hour fast, and after ingestion of the meal. Results: Subjects were aged 35±11 years, had diabetes for 18±11 years, had A1c levels of 8±1% and BMI of 30±8 kg/m2. Short acting insulin doses were higher for subjects receiving insulin detemir versus insulin glargine (p<0.001). Hunger scores, total energy ingested following the 24-hour fast, and Resting Energy Expenditure did not significant differ between the two study conditions. Conclusion: The weight-neutrality of insulin detemir in type 1 diabetes is not attributable to reduced caloric intake following a fast, or to serum satiety factors.
... Gıda alımı, leptin ve ghrelin gibi periferik doyma sinyallerine cevap veren hipotalamik nöropeptitleri içeren karmaşık mekanizma ile düzenlenir. Leptinin beyine doygunluk için temel bir sinyal verdiği ve termojenezi artırdığı kabul edilir, böylece enerji homeostazında önemli bir rol oynar (15)(16)(17). T3 kaynaklı tirotoksikozun hayvan modellerinde, plazma leptin seviyelerinin azaldığı ve / veya doyma merkezinin leptine duyarlılığının azalmasının hiperfajiye katkıda bulunabileceği bulunmuştur (15,16). ...
... Leptinin beyine doygunluk için temel bir sinyal verdiği ve termojenezi artırdığı kabul edilir, böylece enerji homeostazında önemli bir rol oynar (15)(16)(17). T3 kaynaklı tirotoksikozun hayvan modellerinde, plazma leptin seviyelerinin azaldığı ve / veya doyma merkezinin leptine duyarlılığının azalmasının hiperfajiye katkıda bulunabileceği bulunmuştur (15,16). ...
... Integrácia je veľmi zložitý proces, v ktorom majú významnú úlohu mnohé nervové okruhy vychádzajúce z viacerých oblastí mozgu, ktoré spracúvajú množstvo informácií. Predpokladá sa, že hlavným regulačným centrom pre reguláciu príjmu potravy a výdaj energie je hypotalamus (Kalra a spol., 1999;Wilding, 2002). Výstup je odpoveď regulačného centra smerom k periférii, pričom cieľom výstupu je aktivácia takých regulačných a kompenzačných mechanizmov na periférii, aby sa v daných podmienkach dosiahol čo najoptimálnejší stav energetických pomerov v organizme (obr. ...
... mozgovej komory znižuje príjem potravy, zvyšuje výdaj energie a znižuje telesnú hmotnosť. Vo všeobecnosti sa dá povedať, že počas aktivácie NPY/AGRP neurónov dochádza k tlmeniu αMSH/CART a naopak, pričom v oboch prípadoch ide o účinok leptínu (Wilding 2002). αMSH/CART, ako aj NPY/AGRP syntetizujúce neuróny projikujú hlavne do oblasti laterálneho hypotalamu a inervujú HCRT aj MCH neuróny (Elias a spol., 1998). ...
Dávnu túžbu vysvetliť procesy spojené s prenosom informácií medzi
jednotlivými neurónmi, ako aj medzi neurónmi a efektorovými bunkami
sa podarilo čiastočne „naplniťÿ v prvej polovici 20. storočia. Experimen-
tálne sa dokázal chemický základ týchto procesov. Zaviedol sa pojem
neurotransmitery označujúci chemické látky, ktoré umožňujú komuniká-
ciu medzi neurónmi. Zjednodušene možno povedať, že procesy spojené
s ich syntézou, uvoľňovaním, účinkom a odstraňovaním sú „chémiou
mozguÿ, ktorá je spätá so širokým spektrom funkcií nervového sys-
tému. Či už sú to najjednoduchšie senzorické vnemy, reflexné reakcie
alebo vedomie, všetky tieto procesy sú determinované činnosťou týchto
chemických systémov. Narušenie neurotransmiterových systémov môže
mať preto veľmi závažné dôsledky.
Zavedenie sofistikovaných metodík umožnilo výrazný pokrok v po-
znaní jednotlivých „krokovÿ neurotransmisie. V slovenskej odbornej li-
teratúre z posledných rokov nie je publikácia, ktorá by tieto poznatky
reflektovala. Preto sme sa rozhodli pripraviť monografiu, ktorá by sa
venovala procesom súvisiacim s neurotransmisiou.
... The gastrointestinal tract plays a substantial role in the control of food consumption and, consequently, in energy homeostasis (Wolfe & Boylan, 2014). In the different organs and tissues, the expression of peptide hormones promotes a hypothalamic response, mainly in anorexigenic and orexigenic neurons (Wilding, 2002). One of the most important hormones associated with energy balance is leptin, an anorexigenic peptide expressed by adipose tissue, which acts by sensing potential energy stored primarily as triacylglycerol in adipocytes and by controlling food intake (Stanley et al., 2005;Valassi et al., 2008;Zhang et al., 1994). ...
... One of the most important hormones associated with energy balance is leptin, an anorexigenic peptide expressed by adipose tissue, which acts by sensing potential energy stored primarily as triacylglycerol in adipocytes and by controlling food intake (Stanley et al., 2005;Valassi et al., 2008;Zhang et al., 1994). Leptin can modulate the activity of several organs, however, it is influenced by other circulating peptides, such as ghrelin or galanin (Maffei et al., 1995;Wilding, 2002). Leptin acts on the inhibition of NPY/AgRP neurons and the activation of POMC/CART neurons, both directly (there are receptors for leptin in both neuron populations) and for controlling the expression of other peptides involved in the different hypothalamic pathways (Elias et al., 1999;Kristensen et al., 1998;Schwartz et al., 1996). ...
... The regulation of appetite and feeding is a homeostatic mechanism. A powerful and complex physiological system exists to balance energy intake and expenditure, in order that sufficient energy is available and body weight remains stable [2,3]. This system is composed of both afferent signals and efferent effectors. ...
... With weight loss, compensatory physiological adaptations result in increased hunger and decreased energy expenditure, while opposite responses are triggered when body weight increases. This regulatory system is formed by multiple interactions between the gastrointestinal tract (GIT), adipose tissue, and the CNS and is influenced by behavioural, sensorial, autonomic, nutritional, and endocrine mechanisms [2,3]. ...
... It is assumed that leptin signals the brain for satiety and increases thermogenesis. In thyrotoxicosis, experiments with animal models have shown that leptin levels decrease and increase hyperphagia [25,26]. Another mechanism may be related to an increase in TSH values due to HEI resulting in thyroid volume increase. ...
Objective: The aim is to investigate the relationship between thyroid volume measurement and healthy nutrition questionnaire scoring in pregnant women diagnosed with hyperemesis gravi-darum (HEG). Methods: One hundred and fifty pregnant women with a BMI of 15-25 kg/m 2 and between the ages of 17 and 42 who were diagnosed with HEG at 11-14 weeks of gestation were included in the study. Patients with a history of any disease, drug use, and previously diagnosed eating disorders were excluded. All patients were subjected to the Healthy Eating Index (HEI) questionnaire. The cutoff value for HEI score was determined as 80 points. Patients were evaluated in two groups: group 1 (HEI <80 score) and group 2 (HEI 80 score). Complete urine analysis including ketonuria, and thyroid function tests including TSH, T3, and T4 levels were performed for all patients. In addition, the thyroid gland volume of every patient was measured by the same radiologist. Results: Increased thyroid gland volume was significantly associated with lower TSH levels (p ¼ .02) and lower HEI scores (p < .001). On the other hand, it was not significantly associated with ketonuria (p ¼ .47), and parity status (p ¼ .82). Conclusions: In our study, we found that there may be an increase in thyroid volume in pregnant women with HEG with lower TSH levels and eating scores. Thyroid volume may predict the patients with probable eating disorders and further studies on thyroid volume in patients with HEG may contribute to the literature. ARTICLE HISTORY
... This includes the appetite-promoting agouti-related protein (AgRP) neurons and the appetitesuppressing pro-opiomelanocortin (POMC) neurons, which can affect neural signal transmission and alter feeding behavior by controlling downstream melanocortin receptors. In the melanocortin system, leptin binds to the leptin receptor, activating POMC neurons, while inhibiting AgRP neurons [1][2][3][4][5]. Leptin and insulin receptors are highly abundant in AgRP and POMC neurons. ...
Neuronal circuits regulating appetite are dominated by arcuate nucleus neurons, which include appetite-promoting and -suppressing neurons that release the orexigenic neuropeptide agouti-related protein (AgRP) and anorexigenic neuropeptide pro-opiomelanocortin, respectively, to compete for melanocortin receptors to modulate feeding behavior. In this study, we expressed novel agrp promoters, including different lengths of the 5’ flanking regions of the agrp gene (4749 bp) in the zebrafish genome. We used the agrp promoter to derive the enhanced green fluorescent protein (EGFP)-nitroreductase (NTR) fusion protein, allowing expression of the green fluorescence signal in the AgRP neurons. Then, we treated the transgenic zebrafish AgRP4.7NTR (Tg [agrp-EGFP-NTR]) with metronidazole to ablate the AgRP neurons in the larvae stage and observed a decline in their appetite and growth. The expression of most orexigenic and growth hormone/insulin-like growth factor axis genes decreased, whereas that of several anorexigenic genes increased. Our findings demonstrate that AgRP is a critical regulator of neuronal signaling for zebrafish appetite and energy intake control. Thus, AgRP4.7NTR can be used as a drug-screening platform for therapeutic targets to treat human appetite disorders, including obesity. Furthermore, the unique agrp promoter we identified can be a powerful tool for research on AgRP neurons, especially AgRP neuron-mediated pathways in the hypothalamus, and appetite.
... In addition, participants varied in weight status and experience with spicy food which could also contribute to the differences in appetite responses to capsaicin illustrated in the literature. The body's regulation of feeding is a complex interplay between energy intake, body weight, and homeostasis control through gut hormones (62). Therefore, these individual differences could also account for the variations in appetite responses. ...
A preference for chili pepper can be an acquired taste. The contrast between a chili lover and a hater illustrates the complexities involved in forming an appreciation for food that evokes a fiery pain sensation. This narrative review aims to understand the factors behind chili pepper preference formation across the life course and how individual chili pepper preferences can impact eating behaviors and dietary intake. This review was conducted using three databases, yielding 38 included articles. Results suggest five determinants of chili pepper preferences: culture, exposure, gender, genetics, and personality. Collective findings indicate that the strongest influences on preference acquisition include the individual environment from childhood to adulthood and repeated exposure to spicy flavors. With frequent exposure to spicy food, the perceived burn becomes less intense. Culture also influences exposure to chili peppers, with the highest consumption patterns seen within Mexico and some Asia countries. Additionally, males reported having a stronger preference for spicy foods than females. Twin studies illustrated that genetics influenced spicy taste preferences, underscoring the complexity of developing individual taste preferences. As for the impact of capsaicin-containing food on individual eating behaviors and dietary behaviors, appetite effects depend on the dose of capsaicin consumed, but three studies found a change in sensory desires for sweet and fatty foods after finishing a capsaicin-containing dish. Inconsistent results were reported for chili pepper's effects on hunger and satiety after consumption, but changes in specific food desires were observed. The impact of chili pepper on appetite and calories consumed was inconsistent, but the greater amount of capsaicin ingested, the greater the effect. Capsaicin's potential to be used for weight control needs to be further reviewed. In conclusion, evidence suggests that chili pepper preferences may be linked to innate and environmental aspects such as an individual's culture, gender, and genetics. Extrinsic factors like repeated exposure may increase the liking for spicy foods.
... 10 11 These posit that glucose availability plays a fundamental role in the experience of hunger, meal initiation, and satiety. A fall in blood sugar detected by glucose-sensing brain regions 12 is argued to prompt the individual to seek foods with a high glycemic load, whereas insulin secretion through glucose absorption to signal satiety and meal termination via the release of glucagon-like peptide-1. 11 Hence, it is reasonable to expect that a considerable reduction in the availability of glucose in the bloodstream would increase preference for high-carbohydrate foods until euglycemia is achieved. ...
Introduction
Hypoglycemia elicits coordinated counter-regulatory neuroendocrine responses. The extent to which this process involves an increased drive to eat, together with greater preference for foods high in carbohydrate content, is unclear. Our objective was to examine this effect in children and adolescents (age 5–19 years) without diabetes and no prior known experience of hypoglycemic episodes.
Research design and methods
We administered a computerised task designed to examine preference for high-carbohydrate foods (sweet and savory) to pediatric patients (n=26) undergoing an insulin tolerance test as part of the routine clinical assessment of pituitary hormone secretory capacity. The task was completed at baseline and three time points after intravenous infusion of insulin (approximately 7, 20 and 90 min).
Results
Although all patients reached insulin-induced hypoglycemia (mean venous glucose at nadir=1.9 mmol/L), there was moderate evidence of no effect on preference for high-carbohydrate foods (moderate evidence for the null hypothesis) compared with euglycemia. Patients also did not display an increase in selection of foods of high compared with low energy density. Sensitivity of the task was demonstrated by decreased preference for sweet, high-carbohydrate foods after consumption of sweet food and drink.
Conclusions
Results support the view that acute hypoglycemia does not automatically prompt the choice of high-carbohydrate foods for rapid glucose restoration, and further stresses the importance that people and families with children vulnerable to hypoglycemic episodes ensure that ‘rapidly absorbed glucose rescue therapy’ is always available.
... In addition, kisspeptin neurons project to the ARC and exert an effect of reducing food intake by directly stimulating POMC/CART and indirectly suppressing NPY/AgRP neurons [25,26]. Furthermore, NPY/AgRP and POMC/CART neurons of the ARC have been implicated in regulating leptin, ghrelin, and growth hormone effects on energy homeostasis [27,28]. Interestingly, it has been revealed that melatonin affects body weight and energy homeostasis in relation to the above ARC neuron biological process. ...
Constant darkness and constant light exposure often disturb the circadian rhythm in the behavior and energy metabolism of vertebrates. Melatonin is known as the hormonal mediator of photoperiodic information to the central nervous system and plays a key role in food intake and energy balance regulation in vertebrates. The popularly cultured soft-shelled turtle Pelodiscus sinensis has been reported to grow better under constant darkness; however, the underlying physiological mechanism by which darkness benefits turtle growth is not clear yet. We hypothesized that increased melatonin levels induced by darkness would increase appetite and energy metabolism and thus promote growth in P. sinensis. In addition, in order to elucidate the interaction of photoperiod and density, juvenile turtles were treated under three photoperiods (light/dark cycle: 24L:0D, 12L:12D, 0L:24D, light density 900 lux) and two stocking densities (high density: 38.10 ind./m2, low density: 6.35 ind./m2) for 4 weeks, and then the blood and brain tissues of turtles were collected during the day (11:00–13:00) and at night (23:00–1:00) after 2 days of fasting. We examined changes in plasma melatonin levels, food intake (FI), and appetite-related hormones (plasma ghrelin and leptin), as well as growth and energy metabolism parameters such as specific growth rate (SGR), standard metabolic rate (SMR), plasma growth hormone (GH), and thyroid hormone/enzyme activity (plasma triiodothyronine T3, thyroxine T4, and T45′-deiodinase activity). Moreover, we also assessed the responses of mRNA expression levels of food intake-related genes (kisspeptin 1 (Kiss1); cocaine amphetamine-regulated transcript (CART); neuropeptide Y (NPY)) in the brain. The results showed that under high density, SGR was the lowest in 24L:0D and the highest in 0L:24D. FI was the highest in 0L:24D regardless of density. Plasma melatonin was the highest in 0L:24D under high density at night. SMR increased with decreasing light time regardless of density. Most expressions of the measured appetite-related genes (Kiss1, CART, and NPY) were not affected by photoperiod, nor were the related hormone levels, such as plasma leptin, ghrelin, and GH. However, thyroid hormones were clearly affected by photoperiod. T3 level in 0L:24D under high density during the day was the highest among all treatment groups. T4 in 24L:0D under high density during the day and T45′-deiodinase activity in 24L:0D under low density at night were significantly reduced compared with the control. Furthermore, the energy metabolism-related hormone levels were higher under higher density, especially during the day. Together, melatonin secretion is not only modulated by light but also likely to be regulated by unknown endogenous factors and density. Altered plasma melatonin induced by constant darkness and density seems to be involved in the modulation of energy metabolism rather than appetite in the soft-shelled turtle.
... Gastrointestinal tract houses many types of endocrine cells including coloestokinin (CCK), motilin, ghrelin, gastrointestinal polypetide (GIP) and vasointestinal polypeptide (VIP). CCK is transported from the duodenum in response to the presence of food, particularly fatty acids and amino acids (Wilding, 2002). Ghrelin has been identified in non-mammalian species including chickens and stimulates growth hormone (GH) release and suppresses feeding behaviors in neonatal chicks (Saito et al., 2002). ...
... Serine/threonineprotein kinase that acts as a key mediator of the nitric oxide (NO)/cGMP signaling pathway and GMP binding activates PRKG1, which phosphorylates serines and threonines on many cellular proteins (Franz, 2005). In Drosophila melanogaster, the product of the for gene, encoding PKG, might be involved in the regulation of food-related behaviors (Wilding, 2002), and thus, may be related to obesity. The epidemiological study provided indicated that the presence of a high number of metabolic risk factors was negatively associated with urinary cGMP excretion (Renzhe et al., 2007). ...
Genome-wide association studies suggest that there is a significant genetic susceptibility to salt sensitivity of blood pressure (SSBP), but it still needs to be verified in varied and large sample populations. We attempted to verify the associations between single-nucleotide polymorphisms (SNPs) in candidate genes and SSBP and to estimate their interaction with potential risk factors. A total of 29 candidate SNPs were genotyped in the 2,057 northern Han Chinese population from the Systems Epidemiology Study on Salt Sensitivity. A modified Sullivan’s acute oral saline load and diuresis shrinkage test (MSAOSL-DST) was used to identify SSBP. A generalized linear model was conducted to analyze the association between SNPs and SSBP, and Bonferroni correction was used for multiple testing. Mediation analysis was utilized to explore the mediation effect of risk factors. Eleven SNPs in eight genes (PRKG1, CYBA, BCAT1, SLC8A1, AGTR1, SELE, CYP4A11, and VSNL1) were identified to be significantly associated with one or more SSBP phenotypes ( P < 0.05). Four SNPs (PRKG1/rs1904694 and rs7897633, CYP4A11/rs1126742, and CYBA/rs4673) were still significantly associated after Bonferroni correction ( P < 0.0007) adjusted for age, sex, fasting blood glucose, total cholesterol, salt-eating habit, physical activity, and hypertension. Stratified analysis showed that CYBA/rs4673 was significantly associated with SSBP in hypertensive subjects ( P < 0.0015) and CYP4A11/rs1126742 was significantly associated with SSBP in normotensive subjects ( P < 0.0015). Subjects carrying both CYBA/rs4673-AA and AGTR1/rs2638360-GG alleles have a higher genetic predisposition to salt sensitivity due to the potential gene co-expression interaction. Expression quantitative trait loci analysis (eQTL) suggested that the above positive four SNPs showed cis-eQTL effects on the gene expression levels. Mediation analysis suggested that several risk factors were mediators of the relation between SNP and SSBP. This study suggests that the genetic variants in eight genes might contribute to the susceptibility to SSBP, and other risk factors may be the mediators.
... In the central nervous system, the hypothalamus appears to play an important role both in maintaining the feeding behavior and in modulating the level of satiety by integrating the multiple input peripherical signals (Perry and Wang 2012). The regulation of body weight is a homeostatic process; however, this process contains few mechanisms that encourage weight loss, and strongly tends toward the storage of fat and weight gain (Wilding 2002). The food intake and energy equilibrium are regulated by the arcuate nucleus (ARC) (Crespo et al. 2014), which is located on either side of the third cerebral ventricle at the base of the hypothalamus (Kalra and Kalra 2004). ...
Type 2 diabetes and obesity are factors that may cause elevation in the insulin level in the body, possibly leading to insulin resistance. Recent studies have shown the association between insulin resistance and obesity leading to various cancer types including breast, colon, liver, kidney, pancreatic, gastric, and leukemia. The increase in bioavailable insulin-like growth factor 1 (IGF-1) and hyperinsulinemia are instrumental in the formation of tumors in insulin-resistant patients. Overproduction of reactive oxygen species is another cause of developing cancer in insulin-resistant patients as it damages the DNA that contributes to mutagenesis and carcinogenesis. The adipose tissue in diabetic and obese individuals produces high levels of inflammation in cells which promotes tumorigenesis. Hence, weight loss and preventive diabetic therapies offer protective interventions in the development of cancers. In this chapter, we examined the interrelationship between obesity, diabetes, and the mechanism linking to cancer development and also the potential treatment recommendations that may help in controlling cancer.
... In the central nervous system, the hypothalamus appears to play an important role both in maintaining the feeding behavior and in modulating the level of satiety by integrating the multiple input peripherical signals (Perry and Wang 2012). The regulation of body weight is a homeostatic process; however, this process contains few mechanisms that encourage weight loss, and strongly tends toward the storage of fat and weight gain (Wilding 2002). The food intake and energy equilibrium are regulated by the arcuate nucleus (ARC) (Crespo et al. 2014), which is located on either side of the third cerebral ventricle at the base of the hypothalamus (Kalra and Kalra 2004). ...
The study of mechanisms for understanding body weight regulation has led to new insights into the systems governing appetite, food intake, gut and hormonal peptides interactions, and biopeptides. This chapter review summarizes the cumulative research in the last few years that demonstrates the importance of peptides in body weight regulation. Even though some of the research reports here have come from obesity studies, the author believes that their contribution is necessary to understand the physiological systems governing body weight regulation. Besides, this chapter also discusses recent findings and use of biopeptides, compounds that grant functional properties, which could be beneficial for human health. A deeper understanding of biopeptides could be useful if they are to be used as natural treatments in the regulation of body weight, as has been proposed.
... In the central nervous system, the hypothalamus appears to play an important role both in maintaining the feeding behavior and in modulating the level of satiety by integrating the multiple input peripherical signals (Perry and Wang 2012). The regulation of body weight is a homeostatic process; however, this process contains few mechanisms that encourage weight loss, and strongly tends toward the storage of fat and weight gain (Wilding 2002). The food intake and energy equilibrium are regulated by the arcuate nucleus (ARC) (Crespo et al. 2014), which is located on either side of the third cerebral ventricle at the base of the hypothalamus (Kalra and Kalra 2004). ...
Obesity is characterized by excessive accumulation of fats in the adipose tissues. Accumulation of excess fat releases a large number of adipokines that can cause obesity and diabetes mellitus due to irregularity between demand and the production of insulin. Obesity affects many organs and influences the heart, liver, intestines, respiratory organs, endocrine, and reproductive functions. Polydipsia, polyuria, weight reduction, coronary illness, kidney injury, diabetic foot, and diabetic ketoacidosis are pathophysiological manifestations and complications of diabetes. Obesity and overweight also contribute to the immune system dysfunction due to increased secretion of pro-inflammatory cytokines which are also risk factors for many types of cancer.
... In the central nervous system, the hypothalamus appears to play an important role both in maintaining the feeding behavior and in modulating the level of satiety by integrating the multiple input peripherical signals (Perry and Wang 2012). The regulation of body weight is a homeostatic process; however, this process contains few mechanisms that encourage weight loss, and strongly tends toward the storage of fat and weight gain (Wilding 2002). The food intake and energy equilibrium are regulated by the arcuate nucleus (ARC) (Crespo et al. 2014), which is located on either side of the third cerebral ventricle at the base of the hypothalamus (Kalra and Kalra 2004). ...
Obesity and cancer are two of the major highly prevailing health disorders of public health concern. Obesity is a documented strong risk factor for many cancers particularly breast and pancreatic cancers. With a progressively increasing prevalence over the past few decades, obesity and cancer continues to leave a footprint of significant morbidity and mortality across different age groups and populations around the world. The global burden of obesity and cancer on health systems has reached alarming proportions necessitating ongoing research into novel approaches and innovative solutions for prevention and control. Such innovative research endeavors have yielded an evolution of efficacious drug treatments for obesity and cancers over time, some of which are used separately or in combination. This chapter highlights the meeting point between obesity and cancer with focus on their management.
... The thermoregulatory system of young animals has not yet matured, and overly high ambient temperature easily affects the homeostasis of the body, leading to dysregulation of the HPG axis and ultimately affecting the growth and reproduction of the animals and even causing shock or death (Yu, 2009;Sun et al., 2015;Zhou et al., 2016). The hypothalamus is a gray-matter structure at the base of the forebrain that is involved in endocrine secretion and maintaining the balance of metabolic energy in the body (Blouet et al., 2010;Wilding, 2010). GnRH is one of the reproductive hormones synthesized by specific hypothalamic cells with bulging axons at their center, and GnRHs are released into the hypophyseal portal system in a pulsed manner. ...
The hypothalamic-pituitary-gonadal (HPG) axis is a key neuroen-docrine regulation system involved in the growth and reproduction of poultry. High-temperature conditions lead to the physiological dysfunction of target organs of the HPG axis of poultry, ultimately affecting the animals’ growth and development. In this study, we evaluated the effect of heat stress (HS) on the development of cells secreting major reproductive hormones of the HPG axis (i.e., hypothalamus, pituitary gland, ovary, and testis) of Wenchang chicks. Seventy-two one-day-old healthy Wenchang chicks were randomly divided into control (CK) and HS groups. The HS group was placed in a 40 ± 0.5°C artificial climate chamber for heat-stress treatment from 13:00 to 15:00 daily for six consecutive weeks. As development progressed, compared with the CK group, the gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels in the hypothalamus and testosterone (T) levers in the testes of male chicks in the HS group were significantly decreased at three weeks of age (p<0.05). However, GnRH levels in the hypothalamus and estradiol (E2) levels in the ovaries of female chicks in the HS group were variable and significantly lower than those of the CK group at four and five weeks of age (p<0.05). In addition, the LH and FSH levels in the pituitary gland were significantly lower than those in the CK group at two and four weeks of age and at four and six weeks of age, respectively (p<0.05). In brief, HS caused dysfunction of the corresponding target organs of the HPG axis in Wenchang chicks, and this affected the normal growth and development of the cells’ HPG axis.
Keywords:
Heat stress; hypothalamic-pituitary-gonadal (HPG) axis; reproductive hormone; Wenchang chicks
... Four important ''canonical'' neuropeptides are neuropeptide Y (Npy), agouti-related peptide (Agrp), pro-opiomelanocortin (Pomc), and cocaine and (legend continued on next page) ll Article amphetamine-regulated transcript (Cart). Increased expression of Npy and Agrp stimulate food intake, whereas upregulation of Pomc and Cart cause reduced food intake (Ahima and Antwi, 2008;Schwartz et al., 2000;Wilding, 2002). Leptin and insulin interact with these neuropeptides. ...
(Cell Metabolism 33, 888–904.e1–e6; May 4, 2021) In the original version of the article's Figure 7, the Figures 7P and 7O are the same. We mistakenly duplicated the figure 7P during the production process. This error has been corrected online. As this error occurred in figure production and not during data analysis, this error has no impact on the main results or conclusions of this publication. The authors apologize for this error and any confusion it may have caused. [Figure presented] [Figure presented]
... Gastrointestinal tract houses many types of endocrine cells including coloestokinin (CCK), motilin, ghrelin, gastrointestinal polypetide (GIP) and vasointestinal polypeptide (VIP). CCK is transported from the duodenum in response to the presence of food, particularly fatty acids and amino acids (Wilding, 2002). Ghrelin has been identified in non-mammalian species including chickens and stimulates growth hormone (GH) release and suppresses feeding behaviors in neonatal chicks (Saito et al., 2002). ...
... It consists of at least two distinct neuronal populations with opposing effects in appetite regulation. One of them expresses two orexigenic polypeptides, namely, NPY and AgRP, whereas the other expresses the anorexigenic polypeptides, POMC and CART (26). Neuronal projections from these two populations not only extensively interact with other hypothalamic regions containing the PVN, DMH, and LHA (27), but are also influenced by related peripheral hormones, such as leptin, insulin, and ghrelin. ...
Obesity is a prevalent metabolic disease caused by an imbalance in food intake and energy expenditure. Although acupuncture is widely used in the treatment of obesity in a clinical setting, its mechanism has not been adequately elucidated. As the key pivot of appetite signals, the hypothalamus receives afferent and efferent signals from the brainstem and peripheral tissue, leading to the formation of a complex appetite regulation circuit, thereby effectively regulating food intake and energy homeostasis. This review mainly discusses the relationship between the hypothalamic nuclei, related neuropeptides, brainstem, peripheral signals, and obesity, as well as mechanisms of acupuncture on obesity from the perspective of the hypothalamus, exploring the current evidence and therapeutic targets for mechanism of action of acupuncture in obesity.
... Four important ''canonical'' neuropeptides are neuropeptide Y (Npy), agouti-related peptide (Agrp), pro-opiomelanocortin (Pomc), and cocaine and (legend continued on next page) ll Article amphetamine-regulated transcript (Cart). Increased expression of Npy and Agrp stimulate food intake, whereas upregulation of Pomc and Cart cause reduced food intake (Ahima and Antwi, 2008;Schwartz et al., 2000;Wilding, 2002). Leptin and insulin interact with these neuropeptides. ...
The protein leverage hypothesis predicts that low dietary protein should increase energy intake and cause adiposity. We designed 10 diets varying from 1% to 20% protein combined with either 60% or 20% fat, contrasting the expectation that very low protein did not cause increased food intake. Although these mice had activated hunger signaling, they ate less food, resulting in decreased body weight and improved glucose tolerance but not increased frailty, even under 60% fat. Moreover, they did not show hyperphagia when returned to a 20% protein diet, which could be mimicked by treatment with rapamycin. Intracerebroventricular injection of AAV-S6K1 significantly blunted the decrease in both food intake and body weight in mice fed 1% protein, an effect not observed with inhibition of eIF2a, TRPML1, and Fgf21 signaling. Hence, the 1% protein diet induced decreased food intake and body weight via a mechanism partially dependent on hypothalamic mTOR signaling.
... An overview of the main peripheral and central peptides and neurotransmitters involved in mammalian feeding and body mass regulation and their principal sites of synthesis (* synthesised in many additional areas). (Volkow et al., 2011, Akil et al., 1984, Rodgers et al., 2002, Gibson et al., 2010, Wilding, 2002 et al., 2002). ...
As obesity is becoming more prevalent, there is concern for maternal health during pregnancy, parturition and beyond, alongside the impact that maternal obesity has on offspring health. Appetite regulation by gut hormones is one target for obesity ‘treatment’, although little is known about this fundamental system during different female reproductive stages. The main aims of this thesis were to study the orexigenic stomach-secreted hormone ghrelin and the anorexigenic colon-secreted hormones peptide-YY (PYY) and glucagon-like peptide-1 (GLP-1) in female rats during their oestrous cycle, pregnancy and lactation. Changes in gut dimensions during pregnancy and lactation were also studied. In addition, lactation litter sizes were adjusted to explore the effects of different nutritional demands on both the dams and their male and female pups.
Reduced food intake has been reported during oestrus in rats. Here, significantly reduced fasted stomach contents leading into oestrus occurred with significantly increased circulating GLP-1 during proestrus. Ghrelin-positive stomach cells were significantly higher after parturition compared with non-pregnant and pregnant dams; this change may initiate and sustain lactation-associated hyperphagia, with significantly increased plasma ghrelin evident by late lactation. Paradoxical high levels of PYY and GLP-1 were found early in lactation when food intake was high, which may be related to a significant increase in gut growth from early to late lactation. Maternal gut size was significantly increased by late lactation and lactation litter size appeared to influence these changes. Only male offspring had altered satiety hormones, with significantly decreased descending colon PYY and GLP-1 levels when raised in large litters.
In conclusion, gut hormones and gastrointestinal modifications were altered during different reproductive states in females and in their male offspring at weaning. Further study is required to elucidate whether these changes may persist, influencing future health status, and whether they can be reliably modified for therapeutic purposes.
... To explore the roles of CRH, apelin, and GnRH2 in appetite regulation, periprandial (preprandial and postprandial), fasting, and re-feeding experiments were conducted in this study. The hypothalamus is a critical brain region for the control of food intake in mammals and fish (Delgado et al. 2017;Wilding 2002). Therefore, the effects of energy status on the expression of CRH, apelin, and GnRH2 in the hypothalamus of S. davidi were evaluated. ...
Schizothorax davidi is a rare fish in Southwest China and is considered a promising species for aquaculture. Compared with other teleosts, little is known about the endocrine regulation of feeding in this species. In this study, we identified the CRH, apelin, and GnRH2 genes in S. davidi and assessed the effects of different energy statuses on CRH, apelin, and GnRH2 expression. Our results showed that the full-length cDNA sequences of CRH, apelin, and GnRH2 of S. davidi were 995, 905, and 669 bp long, respectively. Furthermore, CRH was mainly expressed in the hypothalamus, telencephalon, and myelencephalon; apelin was highly expressed in the spleen and heart; and GnRH2 mRNA was widely distributed in all examined tissues, with the highest level in the hypothalamus. Notably, the levels of CRH and GnRH2 increased in the hypothalamus at 1 h and 3 h post-feeding, while hypothalamic apelin levels decreased. Conversely, CRH and GnRH2 expression in the hypothalamus significantly decreased after fasting for 7 days and returned to the control levels after re-feeding for 3 or 5 days. In contrast, fasting increased apelin levels in the hypothalamus. Overall, this study suggests that CRH, apelin, and GnRH2 play critical roles in appetite regulation in S. davidi. These results provide an essential groundwork to elucidate the appetite regulatory systems in S. davidi as well as in other teleosts.
... Experimentally, rats prenatally exposed to nicotine have been found to gain more weight postnatally compared to controls that persist into adulthood [141]. This is likely mediated by the effect of nicotine on endocrine system's control of body weight through the hypothalamus (center for appetite regulation) [142,143], which is known to have nAChRs [144]. Supporting this, macaques prenatally exposed to nicotine had altered expression of two hypothalamic peptides that help to regulate satiety and appetite, proopiomelanocortin (POMC) mRNA, and neuropeptide Y [145]. ...
Maternal smoking and nicotine exposure during pregnancy are still considered to be significant global health crises as many decades ago, especially with the emergence of extensive electronic cigarette usage. The detrimental long-term repercussions in the offspring of mothers who smoke during pregnancy are not only concerning in regard to its effects on the lung, such as asthma, chronic lung disease, and increased risk for allergies and infections, but also of great concern are its effects on many other developing organs. For example, there is increased predisposition to metabolic disorders such as obesity and diabetes, heart damage, hypertension, altered internal oxygen sensing, infertility, and malignancies. Convincing evidence shows that the hazardous effects of perinatal tobacco smoke exposure on the development of lung and many other organs, including the transgenerational transmission of asthma, are nicotine mediated; additionally, many other mechanisms such as the reactive oxygen species-mediated damage, altered stress, and metabolic and epigenetic responses contribute. Not only the direct exposure via prenatal and postnatal maternal smoking is a risk, but also exposure to secondhand and thirdhand smoke is a concern, which could be equally or even more dangerous than firsthand smoke exposure. Finally, some of the effects following early-life exposure are not confined only to the exposed offspring but can also be transmitted transgenerationally.
... Insulin sensitizer; circulating levels inversely correlated to dyslipidemias, insulin resistance, metabolic syndrome, obesity, T2D, and cardiovascular diseases [49,50,113] Chemerin Regulates adipogenesis and mature adipocyte metabolism; elevated in obesity, dyslipidemia, T2D, and osteoporosis; a marker of inflammation and metabolic syndrome [114] Hepatocyte growth factor (HGF) Angiogenic and mitogenic effects; linked to vascular diseases; elevated in obese adults and adolescents [115,116] Interleukin (IL)-6 Pro-inflammatory, upregulated in obesity, can exacerbate CVD and metabolic syndrome [113] Leptin Regulates body weight via decreasing appetite and increasing sympathetic nervous activity [49,50,117,118] Neuregulin 4 Regulates energy metabolism; associated with BMI, WHR, triglycerides, and other metabolites; secreted from brown/beige AT [119][120][121] Nerve growth factor (NGF) ...
... A sensação de fome leva à produção de neuropeptídios que aumentam o apetite, enquanto a restrição parcial de alimentos é seguida de excessos compensatórios (Wilding, 2002;Baranowska, Wolinska-Witort et al., 2003 ...
Introdução: a prevalência da obesidade e de outras doenças relacionadas está aumentando em todo o mundo de forma preocupante. Caracterizada pelo aumento do peso corporal ou do acúmulo excessivo de gordura corporal, a obesidade tem sido associada ao aumento da mortalidade decorrente de maior incidência de hipertensão, diabetes e vários tipos de câncer. Os modelos animais fornecem dados fundamentais para a compreensão dos parâmetros básicos que regulam os componentes do nosso balanço energético. Objetivo: esta revisão selecionou artigos que utilizaram modelos animais (ratos e camundongos) de obesidade focando nas principais alterações metabólicas causadas pela obesidade com o objetivo de apresentar os principais modelos utilizados nos últimos 5 anos. Material e Métodos: Foram realizadas duas buscas na base de dados PubMed utilizando as expressões: “obesity” AND “metabolism” AND “animal model” AND “mice” e “obesity” AND “metabolism” AND “animal model” AND “rat”, sendo selecionados os estudos considerados mais relevantes a partir dos critérios: descrição detalhada do modelo experimental e análise dos parâmetros metabólicos de interesse: peso, perfil lipídico e perfil glicêmico. Outras referências foram utilizadas para elucidar melhor os modelos encontrados e também aqueles que não foram citados, mas, que possuem importância no entendimento da evolução dos modelos animais de obesidade. Resultados: A espécie mais utilizada foi o camundongo, o sexo predominante foi o masculino, a faixa etária dos roedores variou de neonatos até 44 semanas e o período de acompanhamento chegou até 53 semanas. A obesidade foi confirmada pelo aumento significativo do peso e na maioria dos estudos foram encontradas alterações no metabolismo lipídico e glicêmico. Encontramos cinco grupos de mecanismos de indução da obesidade porém a maioria dos estudos utilizou dietas hiperlipídicas, modelo que mais se assemelha às alterações metabólicas encontradas em humanos. Conclusão: Investigar as causas e efeitos da obesidade induzida em modelos experimentais pode fornecer uma melhor compreensão da fisiopatologia da obesidade, e proporcionar novas opções de prevenção e tratamento.
... Regulation of energy balance involves an integration of various signals in the hypothalamus and other brain regions. 4,5 Increased food intake tends to correlate with reduced energy expenditure (energy preservation) and vice versa. Such effects are mediated by the sympathetic nervous system, which controls energy expenditure via activation of uncoupling protein-1 in brown adipose tissue. ...
Kyriacou A, Kyriacou A, Makris KC, Syed AA, Perros P. Weight gain following treatment of hyperthyroidism—A forgotten tale. Clin Obes. 2019;e12328.
Hyperthyroidism causes weight loss in the majority, but its effect is variable and 10% of patients gain weight. Its treatment usually leads to weight gain and some studies have reported an excess weight regain. However, there is considerable inter‐individual variability and a differential effect on body weight by different treatments, with some studies reporting more weight increase with radioiodine, and perhaps surgery, compared with anti‐thyroid drugs. The excess weight regain may relate to treatment‐induced hypothyroidism. Furthermore, the transition from hyperthyroidism to euthyroidism may unmask, or exacerbate, the predisposition that some patients have towards obesity. Other risk factors commonly implicated for such weight increase include the severity of thyrotoxicosis at presentation and underlying Graves' disease. Conflicting data exist whether lean body mass or fat mass or both are increased post‐therapy and whether such increments occur concurrently or in a sequential manner; this merits clarification. In any case, clinicians need to counsel their patients regarding this issue at presentation. Limited data on the effect of dietary interventions on weight changes with treatment of hyperthyroidism are encouraging in that they cause significantly lesser weight gain compared to standard care. More research is indicated on the impact of the treatment of hyperthyroidism on various anthropometric indices and the predisposing factors for any excessive weight gain. Regarding the impact of dietary management or other weight loss interventions, there is a need for well‐designed and, ideally, controlled intervention studies.
... To more thoroughly elucidate the mechanism by which GABA regulates FI in these birds, we assessed the effects of GABA on the gene expression levels of select satiety-associated molecules such as NPY, AgRP, POMC, CCK, Ghrelin, and Leptin. FI and energy utilization are regulated by a variety of signalling molecules produced in the central and peripheral tissues in response to nutritional changes (Wilding, 2002). In this study, the observed increases in FI in Cobb birds following GABA supplementation were associated with the regulatory effect of GABA on the gene expression levels of POMC, AgRP and NPY. ...
This study was conducted to investigate the effects of dietary GABA supplementation on blood biochemical parameters, the overall growth performance, and the relative mRNA expression of some FI- regulating genes in broiler chickens. A total of 192, three-day old chicks of mixed sex from two commercial broiler strains (Ross 308 and Cobb 500) were distributed into 2 groups; a control group and GABA-supplemented group (100 mg/kg diet). When the chicks reached 21 days of age, each group of each strain was randomly subdivided into two subgroups: one was exposed to HS (33 ± 2 °C for 5 h/day for 2 weeks), while the other remained at thermoneutral temperature (24 °C). GABA significantly improved bird growth performance under normal and HS conditions, by increasing body weight (BW), weight gain (WG), and FI and significantly reduced the elevated body temperature of birds under HS. GABA supplementation increased FI by reducing the mRNA expression levels of FI-inhibiting neuropeptides, such as POMC, leptin, Ghrelin, and CCK, during HS and by increasing the expression of FI-stimulating neuropeptides such as AgRP and NPY. Moreover, GABA significantly altered FAS and ACC gene expression, resulting in significant increases in abdominal fat content in birds reared normally. In contrast, GABA lowered fat content in Cobb birds and increased it in Ross birds under HS. Therefore, GABA (100 mg/kg diet) is a strong FI-stimulating neurotransmitter and its regulatory effects depend on broiler strain and housing temperature.
... Moreover, acupuncture enhanced the fasting blood Cholecystokinin (CCK) level, a hormone that is involved in feeding behavior through central and peripheral channels. CCK is said to be a neurotransmitter activating satiety signal by affecting the central nervous system after a meal, and there is a close relationship between CCK and ghrelin which starts the meal while CCK ends it [25]. Acupuncture also activated other endocrine-related cytokines such as insulin and epinephrine (Ad) but further studies are needed to confirm its role in the pathophysiology of simple obesity. ...
Simple obesity is a worldwide epidemic associated with rapidly growing morbidity and mortality which imposes an enormous burden on individual and public health. As a part of Traditional Chinese Medicine (TCM), acupuncture has shown the positive efficacy in the management of simple obesity. In this article, we comprehensively review the clinical and animal studies that demonstrated the potential mechanisms of acupuncture treatment for simple obesity. Clinical studies suggested that acupuncture regulates endocrine system, promotes digestion, attenuates oxidative stress, and modulates relevant molecules of metabolism in patients of simple obesity. Evidence from laboratory indicated that acupuncture regulates lipid metabolism, modulates inflammatory responses, and promotes white adipose tissue browning. Acupuncture also suppresses appetite through regulating appetite regulatory hormones and the downstream signaling pathway. The evidence from clinical and animal studies indicates that acupuncture induces multifaceted regulation through complex mechanisms and moreover a single factor may not be enough to explain the beneficial effects against simple obesity.
... It has been found that food intake is increased and physical activity is decreased, particularly in urban populations which results into obesity and associated metabolic disorders [1]. Obesity is attributed to be responsible for various metabolic diseases including hypertension, cardiovascular diseases, metabolic syndrome and type 2 diabetes mellitus [2][3][4]. ...
Obesity is strong contributory factor in incidence and complications of type 2 diabetes and other degenerative disorders. Physical inactivity is associated with obesity and hormone levels. Current study was planned to investigate relationship of physical inactivity with obesity indicators and leptin levels in type 2 diabetics. Type 2 diabetes patients (n=112) visiting public hospitals of Lahore participated in this study. Anthropometric measures and physical activity were recorded using a structured questionnaire. Leptin levels were measured using ELISA. Statistical analysis was carried out to relate parameters of physical activity, obesity indicators and leptin levels. Results showed that type 2 diabetic subjects demonstrate unhealthy body composition and reduced physical activity. Physical activity was associated with leptin levels and obesity indicators. Leptin level was also significantly associated with the obesity indicators. It is concluded that physical inactivity is strongly related with obesity indicators and leptin levels in this population.
... [5][6][7] Leptin concentrations are positively correlated with indices of obesity including body weight, BMI, and waist and hip circumferences and is markedly increased in obese humans and in various animal models of obesity compared to controls or non-obese population. [8][9][10][11] Leptin acts as an afferent satiety signal to inhibit food intake 12 and stimulates energy expenditure. 13 In addition, leptin was found to be involved in blood pressure regulation. ...
Objective: The primary objective of this study was to compare serum NPY and leptin levels between non-pregnant and pregnant women in overall, non-obese, and obese subjects. The secondary objective was to compare these
peptides between non-obese and obese pregnant women.
Methods: Fasting venous blood was collected from non-pregnant women before open abdominal surgery and from pregnant women when admitted to the delivery room during the latent phase of labor.
Results: There were 12 non-obese and 14 obese subjects in the non-pregnant group and 9 non-obese and 30 obese subjects in the pregnant group. Systolic blood pressure (SBP) was comparable, but heart rate (HR) was higher in pregnant
compared to non-pregnant women. Mean±S.E.M serum NPY levels were lower in the pregnant than in the non-pregnant group in overall (0.54±0.02 and 1.34±0.08, respectively), non-obese (0.53±0.05 and 1.23±0.14, respectively), and obese
(0.54±0.03 and 1.43±0.09, respectively) subjects (p
... As energy insufficiency is most likely to negotiation survival, it is not shocking that the most potent pathways in the CNS are decreasing energy expenditure and increase food intake when stores are depleted. The hypothalamus has been accepted as a central area of eating regulation (Wilding 2002). The appetite-regulating system of the brain normally tries to maintain weight even when energy consumption is high. ...
The brain detects changes in energy depots and actuates metabolic and behavioral responses planned to hold energy balance. Hunger, appetite, and satiety are often regarded as functions of the brain. In short, the hypothalamus opponent sets of the neuronal network: stimulatory and inhibitory—appetite neuronal network. This circuit is acted upon by hormone and sensory nervous signals that provide feedback and consolidative processing of nutritional status, energy intake and expenditure. The stimulatory appetite network released orexigenic neurotransmitter which encourages appetite, while anorexigenic neurotransmitter released by inhibitory appetite network decrease appetite. Knowledge about the physiology of appetite has immensely expanded in late years providing potential targets for anti-obesity drug design. This review furnishes a study of the peptides that have been concerned with appetite physiology and energy homeostasis and also includes their therapeutic application (agonist and antagonist).
... The hypothalamus is widely regarded as the center regulating feed intake in animals [39]. Many neural peptides with suppressive and promotive effects on food consumption have been identified in mammals, and similar functions have also been validated in poultry. ...
Background:
The intracerebroventricular injection of visfatin increases feed intake. However, little is known about the molecular mechanism in chicks. This study was conducted to assess the effect of visfatin on the feeding behavior of chicks and the associated molecular mechanism.
Results:
In response to the intraventricular injection of 40 ng and 400 ng visfatin, feed intake in chicks was significantly increased, and the concentrations of glucose, insulin, TG, HDL and LDL were significantly altered. Using RNA-seq, we identified DEGs in the chick hypothalamus at 60 min after injection with various doses of visfatin. In total, 325, 85 and 519 DEGs were identified in the treated chick hypothalamus in the LT vs C, HT vs C and LT vs HT comparisons, respectively. The changes in the expression profiles of DEGs, GO functional categories, KEGG pathways, and PPI networks by visfatin-mediated regulation of feed intake were analyzed. The DEGs were grouped into 8 clusters based on their expression patterns via K-mean clustering; there were 14 appetite-related DEGs enriched in the hormone activity GO term. The neuroactive ligand-receptor interaction pathway was the key pathway affected by visfatin. The PPI analysis of DEGs showed that POMC was a hub gene that interacted with the maximum number of nodes and ingestion-related pathways, including POMC, CRH, AgRP, NPY, TRH, VIP, NPYL, CGA and TSHB.
Conclusion:
These common DEGs were enriched in the hormone activity GO term and the neuroactive ligand-receptor interaction pathway. Therefore, visfatin causes hyperphagia via the POMC/CRH and NPY/AgRP signaling pathways. These results provide valuable information about the molecular mechanisms of the regulation of food intake by visfatin.
... Glucagon is secreted from pancreatic Acells (Holst, 2000) and is responsible for reducing insulin secretion in the digestive tract and inhibiting digestive secretion and motility (Holst and Orskow, 1994). Somatostatin is synthetized from duodenal endocrine cells and from pancreatic D-cells (Brazeau et al., 1973). is conveyed from the duodenum in response to the presence of digested food, particularly fatty acids and amino acids (Wilding, 2002). Serotonin has been proved to influence crypt epithelial secretion and proliferation (Gershon and Tack, 2007). ...
The aim of this study was to detect the regional and mucosal distribution of endocrine cells that secrete gulcagon, somatostatin, Chyholecystokinin-8 (CCK-8), serotonin, secretin, substance P (SP) and histamine in the small and large intestine of New Zealand white rabbit (Oryctolagus cuniculus L.) using immunohistochemical peroxidase-antiperoxidase (PAP) method. It was found that most of the immunoreactive (IR) endocrine cells, which are oval- or spindle-shaped, are spotted in the basal parts of the relevant glands. It was noticed that cells in the lamina epithelialis of small and large intestine is linked to the lumen and that the cells in their glands cannot reach the lumen. Immunoreactive cells for glucagon, somatostatin, serotonin, secretin and SP were identified in lamina epithelialis of the small and large intestine. It was seen that secretin, SP and histamine-IR cells are rarely deployed throughout the intestinal tract. It was determined that somatostatin-IR cells were identified throughout the intestinal tract. In conclusion, the immunohistochemical study shows that gastrointestinal tract of this species contained different types of endocrine cells similar to those found in other vertebrate species. However, some species-dependent unique distributions and frequencies of endocrine cells were also observed in the present study.
... In terms of weight regulation, the diet-regulating hormones leptin and ghrelin exert opposite effects in the hypothalamus and mediate each other 27) . Leptin is secreted by adipose tissues and acts on the satiety center of the hypothalamus to restrict food intake. ...
[Purpose] The purpose of this study is to investigate the effects of circuit exercise on obesity index, appetite regulating hormones and insulin resistance in middle-aged obese women. [Subjects and Methods] The subjects of this study were 26 obese middle-aged women who were selected among participants in exercise class at K Region Health Promotion Center in South Korea and were randomly assigned to the exercise group (n=13; age 50.15 ± 3.82, % body fat 38.79 ± 3.28) and the control group (n=13; age 49.84 ± 2.96, % body fat 37.46 ± 2.51). Circuit exercise consisted of aerobic exercise and resistance exercise for 5 weeks and 50 minutes for 12 weeks. Before and after exercise we measured obesity index, leptin, ghrelin, fasting blood glucose, insulin, and insulin resistance in all subjects. A repeated-measured two-way of variance was performed for comparison of the treatment effects between the exercise and control groups. [Results] Body weight, BMI, and body fat percentage of obese index decreased significantly. Leptin of dietary regulation hormone was significantly decreased and ghrelin was significantly increased. Insulin and insulin resistance was significantly decreased. [Conclusion] Circuit exercise can be viewed as an effective exercise program to induce changes in appetite regulating hormones and to improve insulin resistance by mechanisms of energy homeostasis by weight loss.
... Keywords: food ingestion, food intake, oral intake, olfaction, psychophysical function INTRODUCTION Food intake is controlled by short-acting and long-acting regulatory mechanisms. The aim of the long-acting regulation is to control fat resources to maintain body weight (Wilding, 2002). The short-acting regulation is important for daily food intake. ...
Food intake influences human cognition, olfaction, hunger, and food craving. However, little research has been done in this field to elucidate the effects of different nutrients. Thus, the goal of our study was to investigate the effects of oral ingestion of different nutrient solutions on olfactory, cognitive, metabolic and psychophysical function. Twenty healthy men participated in our study employing a double-blind, cross-over, repeated measurement design. Participants were tested on four different study days. Each day participants received, in randomized order, one of three isocaloric (protein, carbohydrate or fat 600 kcal, 1,500 mL) solutions or a placebo. Olfactory and cognitive tests (monitoring only) were conducted three times, i.e., 60 min before the beginning of nutrient intake, following oral ingestion of the solution and 60, and 240 min after. Psychophysical and metabolic function tests (active grehlin, desacyl ghrelin, insulin, glucagon, glucose, triglyceride, urea) were performed 7 times on each examination day (observation period: −60 min, 0 = solution intake, +60, +120, +180, +240, and +300 min). Ratings of hunger and food craving significantly differed over the observation period with lowest ratings following application of the protein solution. Highest ratings of craving were found following placebo intake. We further observed a significant positive correlation of active grehlin with hunger and fat, protein and sweets craving for each nutrient solution. Active grehlin significantly correlated with carbohydrate craving for carbohydrate and fat solution and with vegetable craving for fat solution only. Hunger hormone levels, hunger and food craving ratings demonstrated that the hierarchical order that appears in satiating efficiencies of isovolumetric-isocaloric ingested macronutrients is protein > fat > carbohydrate. Our study reveals that the type of nutrient exerts a significant influence on metabolic parameters, hunger and food craving.
... This might point to difficult energy storage in the adipocytes, which could trigger Postprandial hunger and satiety response along time in LTG and HTG groups (*significant difference between the groups). * * food intake as an attempt to revert the situation, since the human homeostatic system aims to maintain body storage (1,30). However, despite these differences for the incretin between HTG and LTG groups, there was no impact on ad libitum energy intake. ...
Background:
Considering the possible role of triglycerides (TG), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the regulation of appetite, this study aimed to compare high fat meal-induced response of GIP and GLP-1, appetite scores and ad libitum energy intake in women with obesity, according to postprandial increment in triglyceridemia (∆TG). Methods: Thirty-three no-diabetic women (BMI = 35.0 ± 3.2 kg.m-2) were divided into two groups: Group with ∆TG ≤ median were called "Low TG change -LTG" and ∆TG > median, "High TG change - HTG". Plasma concentrations of GIP, GLP-1 and appetite sensations were measured prior to, and every 30 min for 180 min after ingestion of a high-fat breakfast. An ad libitum lunch was served 3 h after the test meal.
Results:
The AUC incrementalGIP were significant lower in HTG vs. LTG group (p = 0.03). The same was observed for GIP levels at 150 min (p = 0.03) and at 180 min (p < 0.01). Satiety was lower in HTG at 120 min (p = 0.03) and 150 min (p < 0.01). The AUC totalGLP1 were similar between groups and there were no between-group differences for the GLP-1 at each time point. Ad libitum food intake were also similar between groups.
Conclusions:
The HTG group exhibited differences in satiety scores and lower postprandial secretion of GIP, however with no impact on ad libitum food intake in short term.
... For example, dietary NO 3 − has been found to suppress NDF digestion rate (Marais et al., 1988), which may reduce DMI of animals on high-roughage diets, but NO 3 − also leads to nitric oxide (NO) production that may stimulate intake (Morley and Flood, 1991). Absorbed nitrite is a precursor of NO formation and NO is a powerful vasodilator (Umans and Levi, 1995) and metabolic regulator, so NO derived from nitrite may have affected intake as it does in humans (Wilding, 2002). Recently, Callaghan et al. (2014) have argued that higher blood methemoglobin levels may reduce the capability of rangeland cattle to tolerate exercise, but data on exer-cise response in rangeland or feedlot cattle are not yet available. ...
Nitrate supplementation has been shown to be effective in reducing enteric methane emission from ruminants, but there have been few large-scale studies assessing the effects of level of nitrate supplementation on feed intake, animal growth, or carcass and meat quality attributes of beef cattle. A feedlot study was conducted to assess the effects of supplementing 0.25 or 0.45% NPN in dietary DM as either urea (Ur) or calcium nitrate (CaN) on DMI, ADG, G:F, and carcass attributes of feedlot steers (n = 383). The levels of NPN inclusion were selected as those at which nitrate has previously achieved measurable mitigation of enteric methane. The higher level of NPN inclusion reduced ADG as did replacement of Ur with CaN (P < 0.01). A combined analysis of DMI for 139 steers with individual animal intake data and pen-average intakes for 244 bunk-fed steers showed a significant interaction between NPN source and level (P = 0.02) with steers on the high-CaN diet eating less than those on the other 3 diets (P < 0.001). Neither level nor NPN source significantly affected cattle G:F. There was a tendency (P = 0.05) for nitratesupplemented cattle to have a slower rate of eating (g DMI/min) than Ur-supplemented cattle. When adjusted for BW, neither NPN source nor inclusion level affected cross-sectional area of the LM or fatness measured on the live animal. Similarly, there were no significant main effects of treatments on dressing percentage or fat depth or muscling attributes of the carcass after adjustment for HCW (P > 0.05). Analysis of composited meat samples showed no detectable nitrates or nitrosamines in raw or cooked meat, and the level of nitrate detected in meat from nitrate-supplemented cattle was no higher than for Ur-fed cattle (P > 0.05). We conclude that increasing NPN inclusion from 0.25 to 0.45% NPN in dietary DM and replacing Ur with CaN decreased ADG in feedlot cattle without improving G:F. © 2016 American Society of Animal Science. All rights reserved.
... Results herein confirm the positive association of maternal smoking with higher total fat mass in children. A possible mechanism underlying the association between smoking during pregnancy and increased children's adiposity/body weight is abnormal regulation of central endocrine control of body weight homeostasis, particularly abnormal hypothalamic regulation of appetite and energy expenditure (41,42) . ...
Objective:
To identify possibly independent associations of perinatal, sociodemographic and lifestyle factors with childhood total and visceral body fat.
Design:
A representative sample of 2655 schoolchildren (9-13 years) participated in the Healthy Growth Study, a cross-sectional epidemiological study.
Setting:
Seventy-seven primary schools in four large regions in Greece.
Subjects:
A sample of 1228 children having full data on total and visceral fat mass levels, as well as on anthropometric, dietary, physical activity, physical examination, socio-economic and perinatal indices, was examined.
Results:
Maternal (OR=3·03 and 1·77) and paternal obesity (OR=1·62 and 1·78), maternal smoking during pregnancy (OR=1·72 and 1·93) and rapid infant weight gain (OR=1·42 and 1·96) were significantly and positively associated with children's increased total and visceral fat mass levels, respectively. Children's television watching for >2 h/d (OR=1·40) and maternal pre-pregnancy obesity (OR=2·46) were associated with children's increased total and visceral fat mass level, respectively. Furthermore, increased children's physical activity (OR=0·66 and 0·47) were significantly and negatively associated with children's total and visceral fat mass levels, respectively. Lastly, both father's age >46 years (OR=0·57) and higher maternal educational level (OR=0·45) were associated with children's increased total visceral fat mass level.
Conclusions:
Parental sociodemographic characteristics, perinatal indices and pre-adolescent lifestyle behaviours were associated with children's abnormal levels of total and visceral fat mass. Any future programme for childhood prevention either from the perinatal age or at late childhood should take these indices into consideration.
Today, people's food consumption is due to the pleasure they feel for that food rather than their physiological needs. This situation is explained by the view of hedonism. According to this view, the happiness of a person in life is hidden in the pleasure and pleasure he receives from that life. Hedonic hunger, on the other hand, is when a person does not need energy but wants to consume that food for the pleasure he gets from delicious foods. Hedonic hunger prevents the homeostatic pathway when the energy in the body is higher than normal and increases the desire of the person to eat delicious foods. Food enjoyment may induce 'non-homoeostatic' eating. This could potentially contribute to obesity. Obesity has genetic and environmental interactions. It is also a serious and chronic disease. Today, it has become a growing health problem. Since obesity has become a very important health problem that threatens human health, it is very important to understand hedonic hunger in order to establish a meaningful connection between an individual's unhealthy lifestyle and food consumption.
Le syndrome de l’intestin irritable (SII) est un trouble fonctionnel d’origine multifactorielle, impliquant des facteurs environnementaux tels que le stress, l’alimentation et met en jeu un dysfonctionnement de l’axe intestin-cerveau, une micro-inflammation, une dysbiose et une hyperperméabilité intestinale. Le rôle du protéasome dans la régulation de la barrière intestinale au cours du SII a été étudié. De plus, ces troubles fonctionnels intestinaux (TFI) ont également été décrits comme exacerbés chez des patients souffrant d’obésité, dont la physiopathologie est complexe. Néanmoins, les mécanismes impliqués dans cette association restent mal compris et ont donc été recherchés. Dans ce travail, des modèles murins « SII-like » comme le modèle de stress « water avoidance stress » ou WAS et le modèle post-inflammatoire « post-TNBS » ont été utilisés afin d’étudier l’impact d’une inhibition du protéasome sur la régulation de la perméabilité intestinale. L’inhibition pharmacologique du protéasome par le PR-957 ou l’utilisation de souris invalidées pour une sous unité β2i du protéasome limite l’hyperperméabilité intestinale. Une supplémentation orale en glutamine permet également de diminuer la perméabilité intestinale. Une étude protéomique au niveau colique des souris WAS et une étude de l’ubiquitome colique de patients souffrant de SII à profil diarrhéique confirment l’implication du protéasome dans la physiopathologie du SII. Nous avons ensuite cherché à comprendre le lien entre l’obésité et le SII en combinant des modèles d’obésité (génétique et induite par une alimentation riche en graisses ou HFD) et le modèle WAS. Seules les souris HFD présentent une exacerbation de l’hyperperméabilité intestinale et une corticostéronémie plasmatique élevée en réponse au modèle WAS. Des études complémentaires suggèrent que ces résultats sont indépendants de la leptine, de la glycémie et du microbiote intestinal. Nos travaux proposent donc de nouvelles pistes de prise en charge des patients souffrant de SII, par intervention nutritionnelle via la glutamine ou en utilisant le protéasome comme cible thérapeutique. Nous suggérons également un rôle de l’alimentation (riche en graisse) dans le développement des TFI au cours de l’obésité.
Melanocortin-4-receptor (MC4R) gene codes for a G-protein-coupled receptor that is highly expressed in the hypothalamus and involved in the regulation of appetite. Single-nucleotide polymorphisms (SNPs) in the MC4R gene region have been associated with obesity, type 2-diabetes (T2D) and with antipsychotic-induced weight gain. Of these, rs17066842 (G>A) in the MC4R promoter region is the top variant associated with obesity and diabetes. In this study, we investigated the effect of rs17066842 on MC4R expression at various glucose concentrations using reporter gene expression in the SH-SY5Y cell line and regulation of MC4R expression in human cerebral organoids. We observed that higher glucose concentrations significantly reduced MC4R mRNA expression in SH-SY5Y cells. In addition, at high glucose concentrations, the luciferase reporter plasmid containing the MC4R promoter insert with the G-allele of rs170066842 showed significantly reduced activity compared to the A-allele carrying plasmid. The immediate early gene product, early growth-response 1 (EGR-1), was identified to bind to the sequence containing the G-allele at rs17066842 but not to the A-allele-containing sequence. Interestingly, in human induced pluripotent stem cell (hiPSC)-derived cerebral organoids, we observed increased MC4R expression in response to high glucose exposure. These opposite observations might suggest that glucose regulation is complex and may be cell-specific.
This study provides evidence that rs17066842 regulates MC4R gene expression through binding of EGR-1 and that this process is influenced by glucose concentration.
The surging obesity epidemic calls for a deeper understanding of central nervous system (CNS) mechanisms underlying the biologically defended level of body weight. Here, we analyzed global gene expression in four hypothalamic and two brainstem nuclei involved in energy homeostatic control of body weight in diet-induced obese (DIO) and lean rats. Male Sprague-Dawley rats were offered ad libitum chow, or a two-choice diet consisting of a high palatable high sugar/fat diet and chow for 40 weeks. At termination, the hypothalamic arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), paraventricular nucleus (PVN) and lateral hypothalamus area (LHA), as well as the brainstem area postrema (AP) and nucleus of the solitary tract (NTS), were isolated by laser capture microdissection (LCM) followed by mRNA sequencing. Global gene expression analyses revealed a total of 88 differentially expressed genes (DEGs) in DIO rats. Transcriptome changes were mainly observed in the DMH and NTS and associated with neuropeptide signaling and regulation of signaling transduction pathways, suggesting a key role of these brain regions in body weight regulation.
Amaç: Bu çalışmanın amacı, çalışma bölgesinde obez erişkin kohortunda, oreksin-A hormonunun obezite ile ilişkisini değerlendirmektir. Materyal Metot: Çalışmaya, bir şehrimizin Tıp Fakültesi ve Devlet Hastanesi Göğüs Hastalıkları Uyku Laboratuvarlarına başvuran 20-59 yaş arasındaki 261 birey dahil edildi. Vücut kitle indekslerine (VKİ) göre, bireyler beş kategoriye (normal kilolu, fazla kilolu, orta obez, ağır obez ve morbid obez) ayrıldı. Bireylerden alınan plazma örnekleri, ticari olarak temin edilebilen analitik sistemler kullanılarak her bir plazma parametresi analiz edildi. Bulgular: Plazma oreksin-A seviyelerinin VKİ ve C-reaktif protein (CRP) ile negatif korelasyon gösterdiği belirlendi. Orta, ağır ve morbid obez gruplarda, normal ve fazla kilolu gruplara göre oreksin-A düzeyleri anlamlı olarak daha düşük bulundu. VKİ, düşük dansiteli lipoprotein kolesterol (LDL-C) ve CRP ile pozitif korelasyon gösterdi. Orta obez grubun diğer VKİ gruplarına göre karşılaştırıldığında anlamlı olarak yüksek plazma VLDL-C (çok düşük yoğunluklu lipoprotein kolesterol), trigliserid ve total kolesterol seviyelerine sahip olduğu belirlendi. Sonuç: Elde ettiğimiz sonuçlar, oreksin-A'nın periferal olarak etki gösterdiğini doğruladı. Obez bireylerde daha düşük plazma oreksin-A düzeylerinin bulunması, insan enerji metabolizmasının düzenlenmesinde rol oynadığını ve obezitede oreksin-A'nın aktivitesinin bozulduğunu göstermektedir. Obezitenin artmış CRP seviyeleri ile pozitif ilişkili olması, obezite tedavisinin veya sağlıklı kilo kaybının obeziteye bağlı oluşan sistemik inflamasyonun azaltılmasında önemli olduğunu göstermektedir.
From a physiological and animal production standpoint, it is important to know the factors associated with growth and development of the rumen. Calf transition from monogastric into ruminant involves structural and physiological changes of the digestive system. This process involves hormones that affect both the orexigenic (ghrelin) and metabolic phases, and also nutrient utilization (i.e., insulin and growth hormone). The aim of this study was to monitor growth of calves between birth and six months of age and determine serum ghrelin, growth hormone, and insulin, in three breeds. Eight animals were selected from each breed (Harton del Valle, Holstein, and Brahman). Body weight was measured and blood samples collected every 30 days. Protein was analyzed by direct refractometry, insulin and ghrelin by radioimmunoassay (RIA), glucose by enzymatic colorimetry, and growth hormone (HG) by ELISA. A factorial design with two main effects (animal breed and sampling age) was used, blocking by weight groups. Analysis of variance showed differences (p
The modulators that diminish appetite and increase metabolic calorie needs at hypothalamus level are synthesized in different tissues: gastrointestinal system (glucagons-like peptide-1, pancreatic polypeptide, peptide YY, cholecystokinin and oxynt-modulin), the endocrine system (insulin, beta effects of adrenalin, and estrogens), adipose tissue (leptin, visfatin and omentin-1), peripheral nervous system (noradrenaline beta effects) and central nervous system (corticotropin released hormone, melanocortin, agouti protein, cocacine-amphetamine-regulated transcript and MCH). Those factors increasing appetite and lower basal metabolism comes from gastrointestinal system (ghrelin and growth hormone release hormone from pancreas), and central nervous system (neuropeptide Y, orexins and cannabinoids). In the hypothalamus, the neural and neuroendocrine afferents are integrated with the purpose of regulate appetite (hunger or satiety signals), and metabolic needs (increasing or decreasing basal metabolism and brown adipose tissue thermoregulation efficacy) according to body energy balance. The arcuate nucleus contains 2 main cellular systems: one rich in proopiomelanocortin (precursor of alpha melanocytes stimulating hormone and agonist of melanocortin 3 and 4 receptors), which decreases appetite, and other rich in neuropeptide Y and agoutirelated peptide which increase appetite.
The aim of this study is to determine glycemic index and weight management in female athletes. This is a randomised cross-over study investigating the effects of the following ad libitum low and high GI diet with 50% energy from CHO for 4 weeks on insulin sensitivity and blood lipids in overweight female's athletes. All subject needs to report to the laboratory for preliminary test and the actual experimental trials. The test will involve the measurement of body composition, RMR, fasting blood and ECG of the subject. Subjects will be explain thoroughly about the exercise protocol and equipment used during the experimental trials. The expected outcome for the study is to identify and plan better strategies for weight loss in female athletes. Hence, the result will produce a proper way of planning a program to suit the needs of athletes. The glycemic index was not identified as risk factors for overweight and adiposity in this cross-sectional study.
Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined1. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse2,3. We have previously described a woman with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. GlyArg483 prevents processing of proPd and leads to its retention in the endoplasmic reticulum (ER). AC+4 of the intron-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
Exogenous cholecystokinin (CCK) decreases food intake and causes satiety in animals and man. However, it has not been established that endogenous CCK causes satiety or whether the response is mediated by peripheral-type (CCK-A) or brain-type (CCK-B) receptors. The development of potent and selective antagonists for CCK-A (MK-329) and CCK-B (L-365,260) receptors now allows these issues to be addressed. The CCK-A antagonist MK-329 and the CCK-B antagonist L-365,260 increased food intake in partially satiated rats and postponed the onset of satiety; however, L-365,260 was 100 times more potent than MK-329 in increasing feeding and preventing satiety. These results suggest that endogenous CCK causes satiety by an agonist action on CCK-B receptors in the brain.
Neuropeptide Y (NPY) has recently been localized in the rat hypothalamus. We have evaluated the effects of NPY on hypothalamic and pituitary function by injecting NPY into the third ventricle in vivo and by examining its action on perifused pituitary cells in vitro. Injections of NPY into the third ventricle of conscious ovariectomized rats led to a dramatic and highly significant reduction in plasma luteinizing hormone (LH) relative to pretreatment levels in these animals or to those of controls injected with physiological saline. Significant inhibition was obtained with doses ranging from 0.02 to 5.0 micrograms (4.7-1175 pmol) of NPY. These inhibitory effects on LH release were dose dependent and lasted for at least 120 min after injection of 5.0 micrograms of NPY. Intraventricular injection of NPY also significantly decreased plasma growth hormone; however, the threshold dose was 2.0 micrograms (470 pmol), a dose 100-fold greater than the lowest dose that inhibited LH release. Plasma follicle-stimulating hormone was unaffected by injection of NPY. NPY (10(-6) and 10(-7) M) stimulated secretion of LH, growth hormone, and follicle-stimulating hormone from perifused anterior pituitary cells loaded in a Bio-Gel P-2 column. These results indicate that NPY acts on structures adjacent to the third ventricle to inhibit the secretion of LH and growth hormone but not follicle-stimulating hormone, whereas it can directly stimulate the secretion of all three hormones from the cells of the anterior pituitary in vitro. Since NPY has been found in the hypothalamus and median eminence, it is quite likely that it plays a physiologically significant role at both hypothalamic and pituitary sites: influencing secretion of pituitary hormones.
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.)
The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
With the escalation of obesity-related disease, there is great interest in defining the mechanisms that control appetite and
body weight. We have identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular
treatment of mice with fatty acid synthase (FAS) inhibitors (cerulenin and a synthetic compound C75) led to inhibition of
feeding and dramatic weight loss. C75 inhibited expression of the prophagic signal neuropeptide Y in the hypothalamus and
acted in a leptin-independent manner that appears to be mediated by malonyl–coenzyme A. Thus, FAS may represent an important
link in feeding regulation and may be a potential therapeutic target.
The adipocyte-specific hormone leptin, the product of the obese (ob) gene,regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure1, 2, 3, 4. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family5, 6, 7. In rodents, homozygous mutations ingenes encoding leptin1 or the leptin receptor6 cause early-onsetmorbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadism8. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity9. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
1Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin- noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia.2Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period.3Sibutramine (10 mg kg−1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the 1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg−1, i.p.), and partially antagonized by the β1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg−1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg−1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg−1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg−1, p.o.).4By contrast, the 2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg−1, i.p.) and the β2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg−1, i.p.) did not reduce the decrease in food intake induced by sibutramine.5These results demonstrate that β1-adrenoceptors, 5-HT2A/2C-receptors and particularly 1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.British Journal of Pharmacology (1997) 121, 1613–1618; doi:10.1038/sj.bjp.0701311
Nondeprived adult rats were familiarized with a highly palatable diet (powdered small animal diet mixed with sweetened condensed milk and water). The palatability of food was such that it induced vigorous feeding responses, 15-20 g food consumed within the first 30 min of access. In partially-satiated male rats, the kappa receptor agonists EKC and U-50,488 (subcutaneously administered) produced large increases in food consumption in the first 30 min of access, post-injection. In experiments with naloxone and WIN 44,441-3, we found that the effects of naloxone (0.01-10 mg/kg; S.C.) were crucially dependent on the sex and dietary history of the animals. Male, obese rats were most sensitive to naloxone's anorectic effect. Lean females were completely insensitive. WIN 44,441-3 (0.01-10 mg/kg, S.C.) had no effect on food intake in any group of animals.
The effects of NG-nitro-L-arginine, an inhibitor of brain nitric oxide (NO) synthase, on central serotoninergic system were studied in male obese Zucker rats and in their lean age-matched controls (FA/?; FA/FA), both groups aged 14 weeks. Acute injection of NG-nitro-L-arginine (50 mg/kg i.p.) or repeated administration of NG-nitro-L-arginine (50 mg/kg i.p. daily, for 7 days) reduced food intake and body weight in obese rats. Acute administration of NG-nitro-L-arginine reduced food intake in lean rats. However, lean rats showed tolerance to the NG-nitro-L-arginine effects after repeated administration. NG-Nitro- L-arginine administration significantly increased serotonin metabolism in the cortex, diencephalon and medulla-pons of obese Zucker rats after either acute or repeated administration of NG-nitro-L-arginine. In contrast, NG-nitro-L-arginine increased serotonin metabolism in lean rats only after acute administration, and the appearance of tolerance to NG-nitro-L-arginine anorectic effects paralleled the failure of NG-nitro-L-arginine to increase serotonin metabolism. The present data extend our previous findings indicating that NG-nitro-L-arginine possesses anorectic activity in obese Zucker rats, and clearly suggest that the central serotoninergic system mediates the anorexia induced by inhibitors of brain NO synthase.
Neuropeptide Y (NPY), a putative neurotransmitter abundant in the brain, has recently been shown to act within the hypothalamus, inducing a powerful eating response and a specific appetite for carbohydrates. In the present study, NPY (235 pmol) injected bilaterally in the paraventricular nucleus three times a day for 10 days caused approximately a two-fold increase in daily food intake, a six-fold increase in the rate of body weight gain and a three-fold increase in the body fat of female rats. Subsequently, the food intake and body weight of these subjects decreased precipitously, reaching control levels 20 days postinjection. These findings, demonstrating that exogenous NPY is capable of overriding mechanisms of satiety and body weight control, suggest that disturbances in NPY function may play a role in some disorders of eating behavior and body weight regulation.
The effect of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight was assessed in adult, non-obese Wistar rats. The daily administration of SR 141716 (2.5 and 10 mg/kg; i.p.) reduced dose-dependently both food intake and body weight. Tolerance to the anorectic effect developed within 5 days; in contrast, body weight in SR 141716-treated rats remained markedly below that of vehicle-treated rats throughout the entire treatment period (14 days). The results suggest that brain cannabinoid receptors are involved in the regulation of appetite and body weight.
The aim of this study was to investigate whether infusion of bombesin, when combined with a gastric preload, influence satiety and foot intake in obese and lean healthy women.
Double blind, placebo controlled study.
Department of Gastroenterology, Leiden University Medical Center, The Netherlands.
Obese (n = 7) and lean (n = 7) healthy women.
Intravenous infusion of bombesin (0.09 nmol/kg ideal weight/h) or placebo for 165 min. Gastric preload of banana slices was administered at time 60 min. Meal ingestion started at time 75 min (banana slices). Food intake was calculated and satiety was measured by visual analog scales.
During infusion of bombesin the amount of food eaten by the lean individuals (193+/-37 g) was significantly reduced compared to saline infusion (365+/-42 g, P < 0.05). However, bombesin induced no significant feeding suppression in obese women when compared to saline (241+/-46 vs 301+/-45 g, respectively). The decrease in food intake during bombesin infusion compared to saline was significantly greater in lean subjects (173+/-30 g) than in obese subjects (59+/-35 g; P < 0.05). Only in lean subjects subjective preprandial hunger feelings were significantly affected by bombesin infusion.
Infusion of bombesin, when combined with a gastric preload, inhibits food intake and increases satiety in lean women. Obese women are less sensitive for these bombesin induced satiety effects.
Administration of methyl palmoxirate (MP), an inhibitor of fatty acid oxidation, stimulates eating behavior in rats. Fos immunohistochemistry was used to determine neural pathways that may play a role in the eating response to MP. The number of cells showing Fos-like immunoreactivity (Fos-li) was quantified by computerized image analysis. MP treatment, at a dose that increased food intake (10 mg/kg, p.o.), induced Fos expression in the nucleus of the solitary tract, area postrema, lateral parabrachial nucleus, central lateral nucleus of the amygdala, dorsal lateral bed nucleus of the stria terminalis, and the paraventricular nucleus of the hypothalamus. The results suggest that MP activates an afferent pathway projecting from the hindbrain to the forebrain, which may be involved in the eating response after MP treatment.
Body adiposity is normally maintained within rigid limits1-3.
Although it is not clear that this regulation fits a strict negative
feedback pattern, animals do maintain a relatively constant body
adiposity4. It has been postulated that this regulation is
mediated by some signal which informs centres controlling food intake,
probably located in the brain, as to the present state of
adiposity5,6. The identity of the signal is unknown, but the
direct correlation between body adiposity and basal insulin levels in
the plasma7-9, suggests insulin as a possible candidate. This
hormone is present in the cerebrospinal fluid (CSF) of many
species10-13, and is a slow integral over time of the level
within the plasma14. Thus, the level of insulin in the CSF is
relatively resistant to short-term plasma fluctuations of insulin. Obese
humans have higher levels of CSF insulin than lean controls and the CSF
insulin level of both obese and lean humans is reduced proportionately
after a prolonged fast15. We have therefore
postulated16 that the feedback system responding to body
adiposity uses the concentration of insulin in the CSF as a major
signal. Additional support for such a role is found in recent reports
that insulin receptors are present in several regions of the brain and
spinal cord17-20. We now present additional evidence for our
hypothesis by showing that in baboons the infusion of exogenous insulin
into the CSF elicits a reliable and predictable decrease in food intake
and body weight.
Bombesin (BBS) is a tetradecapeptide originally isolated from amphibian skin1. BBS-like immunoactivity is widely distributed in mammalian gut2-5, and plasma levels have been shown to rise sharply following feeding (ref. 6 and V. Erspamer, personal communication). The physiological actions of BBS are unknown. We have previously shown that the classic gut hormone cholecystokinin (CCK) is a powerful and specific suppressor of food intake7-9. Although CCK and BBS lack common amino acid sequences, they have certain common actions on gut viscera10,11. We have now shown that BBS also suppresses food intake, and we compare its action with that of CCK.
These studies demonstrate that the competitive antagonist of nitric oxide synthesis, L-NG-nitro-arginine methyl ester (NO Arg ME), produces an L-arginine reversible decrease in food intake in mice. NO Arg ME also blocked the feeding effect of the potent orexigenic peptide, neuropeptide Y. NO Arg ME produced weight loss when administered over 5 days. The studies suggest that nitric oxide is a physiological modulator of food intake and that nitric oxide synthetase inhibitors may be useful in the management of obesity.
Neuropeptide Y (NPY) concentrations were measured by radioimmunoassay in eight microdissected hypothalamic regions of obese (fa/fa) and lean (Fa/?) Zucker rats. Freely fed obese rats showed significant (40-100%) increases in NPY concentrations in several regions, notably the paraventricular, ventromedial, and dorsomedial nuclei and the arcuate nucleus/median eminence, compared with lean rats. Hypothalamic NPY concentrations were not affected in either obese or lean rats by food restriction, which caused 25% weight loss over 3 wk. Refeeding to initial weight significantly increased NPY levels in the ventromedial and dorsomedial nuclei in lean rats but did not significantly alter NPY concentrations in any hypothalamic region in obese rats. These observations indicate fundamental differences in the regulation of hypothalamic NPY between obese and lean Zucker rats. NPY injected into the paraventricular nucleus and other regions causes hyperphagia, obesity, and increased secretion of insulin, glucagon, ACTH, and corticosterone. These behavioral and neuroendocrine abnormalities all occur in the obese Zucker syndrome and may be due to increased NPY-ergic activity in the hypothalamus.
Nitric oxide (NO) may be an intercellular modulator within the central nervous system. L-arginine, which results in NO synthesis, increased food intake in mice while the inhibitor of NO synthesis, L-NG-nitro arginine (L-NO Arg) inhibited food intake in food deprived mice. L-arginine, but not D-arginine, partially reversed the inhibitory effect of L-NO Arg on food intake. These findings suggest the possibility that NO may be a physiological modulator of food intake and that the possibility of exploring the utility of L-NO arg in the treatment of obesity should be explored.
To assess the role of cholecystokinin (CCK) receptors in mediating the satiating effect of an oral preload, overnight food-deprived rats (n = 7) were given access to a high-carbohydrate liquid diet for 40 min. At the end of 40 min, food was removed and rats were injected subcutaneously (SC) with devazepide (DVZ; 1 ng/kg-1 mg/kg), an antagonist selective for the CCK-A receptor, or its vehicle, 0.5% carboxymethylcellulose (CMC). Thirty min after injection, rats were given access to the same liquid food for 60 min. DVZ increased food intake significantly. Furthermore, the effectiveness of a very low dose of DVZ (10 ng/kg) is strong evidence that the effect of DVZ was specific for CCK-A receptors. Three of the rats that increased food intake after DVZ were also tested with L-365,260, an antagonist selective for the CCK-B receptor (10 ng/kg-100 micrograms/kg). L365,260 did not increase food intake significantly. These results confirm and extend previous reports that CCK-A receptor blockade increases food intake after an oral preload. They do not, however, demonstrate a role for the CCK-B receptor in mediating the satiating effect of ingested food under the same experimental conditions.
To investigate the effects of neuropeptide Y (NPY) on sympathetic nerve activity to interscapular brown adipose tissue (IBAT), we injected NPY into the third cerebroventricle (icv), medial preoptic area (MPOA), anterior hypothalamic area (AHA), paraventricular hypothalamic nucleus (PVN), ventromedial hypothalamic nucleus (VMN), and lateral hypothalamic area (LHA) of anesthetized rats. Multiunit discharges from sympathetic nerves to IBAT were recorded electrophysiologically. The icv injection of NPY suppressed sympathetic nerve activity in a dose-dependent manner, followed by a gradual recovery. The microinjection of NPY (25 pmol) unilaterally into the PVN also significantly suppressed the sympathetic nerve activity to IBAT. In contrast, microinjection of NPY into the MPOA significantly increased the sympathetic nerve activity. The injection of saline into either the PVN or MPOA had no significant effect on sympathetic nerve activity. The microinjection of NPY (25 pmol) into the AHA, VMN, or LHA did not change sympathetic nerve activity to IBAT. We conclude that central administration of NPY affects the sympathetic nerve activity to IBAT and that the suppressive effect of NPY, which may act in part through the PVN, is dominant to the stimulatory effect. The result is consistent with the hypothesis that NPY is a neurochemical modulator of the sympathetic nervous system which controls energy expenditure in IBAT.
By acting in the brain, insulin suppresses food intake, whereas neuropeptide Y (NPY) has the opposite effect. Since fasting increases NPY gene expression in the hypothalamic arcuate nucleus (ARC) and also lowers circulating insulin levels, we hypothesized that the anorexiant effect of insulin could result from insulin inhibition of NPY gene transcription in the ARC. Therefore, we determined whether the administration of insulin (200 mU per 12 hrs) into the 3rd cerebral ventricle of lean (Fa/Fa) female Zucker rats (n = 5) during 48 hrs of food deprivation reduces the expression of preproNPY mRNA in the ARC compared to vehicle-treated controls (n = 5). Coronal sections of rat brain were hybridized with an oligonucleotide probe complementary to preproNPY mRNA and apposed to x-ray film. Hybridization was quantified in both the ARC and the hippocampal dentate gyrus by computerized image analysis of the resulting autoradiographs. Central insulin significantly reduced the area of hybridization in the ARC (0.235 +/- 0.017 mm2; mean +/- SE) compared to vehicle-treated controls (0.331 +/- 0.037 mm2; p less than 0.05), but was without effect in the hippocampus. Thus, insulin reduced the expression of mRNA for NPY specifically in the ARC. Since the genetically obese (fa/fa) Zucker rat is insensitive to the anorexiant effect of insulin and over-expresses NPY in the ARC, we next tested the hypothesis that insulin does not suppress NPY mRNA expression in the ARC of these rats. Consistent with this hypothesis, central insulin administration to obese Zucker rats during 48 hrs of food deprivation (n = 6) did not lower hybridization area in the ARC compared to vehicle alone (n = 4) (0.286 +/- 0.036 vs. 0.248 +/- 0.019 mm2; p greater than 0.05). We conclude that insulin suppresses the expression of mRNA for NPY in the ARC of fasted lean but not obese Zucker rats. Regulation of hypothalamic NPY gene expression by insulin may account for its anorexiant effect, and a defect in this action may contribute to certain forms of obesity.
Transient declines in blood glucose concentration are proposed to be signals that induce meal initiation in free-feeding rats. This assertion is based upon the following evidence: (1) the observation that a transient declines in blood glucose preceded each meal; (2) attenuation of transient decline in blood glucose by i.v. glucose led to a delay in meal initiation; (3) declines in blood glucose were endogenous and that if access to food was denied during and after a decline in blood glucose and then restored, meal initiation was not observed until after another transient decline; (4) experimental induction of transient declines in blood glucose that mimic the pattern of blood glucose prior to spontaneous meals resulted in meal initiation; (5) a transient spike of insulin was observed just prior to the transient decline in blood glucose that precedes meal initiation; (6) in rats with total subdiaphragmatic or hepatic vagotomy, normal transient declines in blood glucose occurred but meal initiation was observed only after approximately 55 percent of the declines; (7) since infusions of other substrates (amino acids, ketone bodies, hexoses) failed to delay or block meal initiation, this signal appears to be specific for glucose. These studies, conducted in our laboratories over the past five years, suggest that transient declines in blood glucose with the necessary shape and magnitude are reliable signals for feeding that are detected by central nervous system glucose receptive elements and are mapped into meal initiation.
Preembedding immunoperoxidase staining methods were used to allow ultrastructural localization of neuropeptide Y (NPY) and galanin immunoreactivity (IR) in the paraventricular nucleus (PVH) of the rat hypothalamus. NPY-IR was localized exclusively in axons and axon terminals which could be grouped into three types: (1) symmetric axo-somatic contacts predominantly with parvocellular neurons, many of which displayed neurosecretory specializations, (2) predominantly asymmetric contacts onto larger dendritic processes, including some of magnocellular neurosecretory neurons, and (3) predominantly symmetric contacts with small dendritic and spine-like profiles. Galanin-IR terminals displayed a more limited distribution and formed both symmetric and asymmetric contacts with parvocellular neurons, and primarily asymmetric contacts with larger dendritic shafts. Numerous dendritic and somatic profiles, including those of some magnocellular neurosecretory neurons, were lightly stained for galanin IR. These results establish that NPY and galanin IR afferents form a variety of conventional synaptic contacts in the PVH. The two peptidergic terminal types differed with respect to the frequency of their interaction with various postsynaptic targets and/or their distribution upon them. Both peptidergic inputs arise at least in part from brainstem catecholaminergic neurons, and the relationship of the present results to the fine structure of catecholaminergic terminals is discussed.
Recent studies have found that the hyperphagia and obesity resulting from lesions of the ventromedial hypothalamus (VMH) are both reversed and prevented by complete adrenalectomy. Several previous experiments, however, reported little or no suppression of VMH weight gain in hypophysectomized (HYPOX) rats. This study directly compared the effects of hypophysectomy and adrenalectomy on hypothalamic obesity in adult female rats. Complete adrenalectomy (i.e, stress-induced plasma corticosterone less than 1.0 micrograms/dl) totally suppressed abnormal weight gain in the first 20 days after VMH lesions but did not affect intracranial self-stimulation. Hypophysectomy also resulted in suppression of weight gain, but the HYPOX-VMH rats nevertheless gained significantly more weight than HYPOX rats with sham lesions. However, the HYPOX-VMH animals had very low levels of plasma corticosterone and adrenocorticotropin (ACTH) (from residual pituitary tissue or of diencephalic origin), and incompletely adrenalectomized rats with similar low levels of plasma corticosterone gained an equal amount of weight after VMH lesions. It was concluded that adrenal glucocorticoid hormones play a largely permissive role in the VMH syndrome, with only very small levels required for the manifestation of obesity.
This study evaluates the role of adrenal hormones in the development of hyperinsulinaemia and impaired glucose homeostasis in genetically obese hyperglycaemic C57BL/6J ob/ob mice. Lean (+/?) and obese mice were bilaterally adrenalectomised or sham operated at 5 weeks of age, and glucose tolerance was examined after 7 and 14 days. Adrenalectomy temporarily reduced food intake and body weight gain in lean mice, and improved glucose tolerance without a significant change in plasma insulin concentrations at both intervals studied. In obese mice adrenalectomy permanently reduced body weight gain and food intake to values comparable with lean mice. Glucose tolerance was improved in adrenalectomised obese mice at both intervals studied, resulting in plasma glucose concentrations similar to adrenalectomised lean mice. Plasma insulin concentrations during the tolerance tests were reduced in adrenalectomised obese mice, but remained higher than in lean mice. Adrenalectomy did not improve the poor insulin response to parenteral glucose in obese mice. The results indicate that adrenal hormones play an important role in the development of glucose intolerance and contribute to the hyperinsulinaemia in obese (ob/ob) mice, in part by promoting hyperphagia.
Systemically administered bombesin reduces food intake in rats, mice, baboons, and humans. The mechanism of action is unknown. We report here that presumed neural disconnection of the gastrointestinal tract from the brain blocked the reduction of food intake by exogenous bombesin at a test meal in rats. We also found that bombesin increased the postprandial intermeal interval, and that this effect was not blocked by neural disconnection.
A system is described for automatically changing the solutions surrounding skinned muscle fibers at a controlled temperature. The system consists of a complex muscle chamber and solenoid valve-controlled vacuum-driven syringe pumps. The chamber has a muscle trough, a conduit for circulating coolant, and channels for precooling solutions. After traveling through the cooling channels, the solutions are injected into one end of the muscle trough and removed by suction at the other. The volume of the trough (approximately 40 microliter) is kept as low as possible to minimize the amount of solution required for complete solution exchange (approximately 400 microliter). Solution changes are complete within 400 ms. The timing of the sequence of solution changes is precisely controlled by digital timers that activate the solenoid valves of the pumps. By exposing the fibers briefly to a high concentration of free calcium and then changing to a buffered calcium solution, it is possible to achieve steady tension levels in 1-2 s, even when partially activating the fibers. Such rapid partial activation is possible because the exposure to free calcium can be precisely timed. The timers also allow the solution changes to be synchronized with other perturbations.
THE lateral hypothalamic region (LH) is generally referred to as the feeding centre of the brain in the regulation of food intake, and many authors consider the ventromedial hypothalamic nucleus (VMH) to be the satiety centre1. Various hypotheses have been put forward to explain how the cells of these centres are activated, and one of these is the glucostat theory1. The existence of hypothalamic chemoreceptors, such as those sensitive to the concentration of blood glucose, can be inferred from studies of single unit discharges induced by intravenous or intracarotid administration of various solutions2-4 and from work on selective gold thioglucose lesions5. It has, however, been impossible to determine which centre is activated or inhibited first or whether both centres are modulated directly by a change in the concentration of blood glucose, because of the reciprocal relations which exist between the activities of the VMH and the LH2,6. We report here the direct effects of glucose on individual cells of the VMH and LH, which we studied by means of electro-osmotic applications of glucose from micropipettes-the method used by Krnjevic and Whittaker7 in other regions in the brain.
