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Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight
Abstract
Orexins are recently identified neuropeptides, and have been shown to increase food intake when administered intracerebroventricularly. We examined the effects of chronic administration of orexin in rats by continuous intracerebroventricular administration by means of an osmotic minipump. Continuous administration of orexin-A (0.5 nmol/h) for 7 days in rats resulted in a significant increase in food intake in the daytime. Daytime food intake increased to 180% of the control value. However, it resulted in a slight decrease nighttime food intake as compared with vehicle-treated rats. The total amount of food intake per day was almost comparable with that of vehicle-administered rats. The gain of body weight and blood glucose, total cholesterol and free fatty acid levels were normal. Chronic orexin-A treatment did not cause obesity in rats. We observed abnormal behavior during the daytime after starting administration of orexin-A; these rats kept awake during the daytime. Our present observation showed that continuous administration of orexin-A could not overcome the regulation of energy homeostasis and body weight. However, orexin-A might be implicated in short-term, immediate regulation of feeding behavior.
... Moreover, ablation of orexin neurons using either genetic manipulation (Hara et al. 2001) or toxins (Mistlberger et al. 2003) results in hypophagia. On the other hand, acute intracerebroventricular (i.c.v.) injection of orexin A significantly increases food intake (Akimoto- Takano et al. 2005;Alvarez-Crespo et al. 2013;Asakawa et al. 2002;Choi et al. 2010;Crespo et al. 2008;Edwards et al. 1999;Espana et al. 2002;Farr et al. 2005;Ford et al. 2005;Haynes et al. ,1999Haynes et al. , , 2000Jain et al. 2000;Jorgensen et al. 2005;Karasawa et al. 2014;Kokare et al. 2006;Li et al. 2015;Lubkin & Stricker-Krongrad, 1998;Monda et al. 2003;Moreno et al. 2005;Sahu, 2002;Sakurai et al. 1998;Shiraishi et al. 2000;Takano et al. 2004;Tsuji et al. 2011;Yamanaka et al. 2000;Zheng et al. 2005), whereas continuous infusion into the lateral ventricle increases daily food consumption during daytime hours (Haynes et al. 1999;Yamanaka et al. 1999). Furthermore, intranasal delivery of orexin A produces similar effects (Dhuria et al. 2016). ...
... These results suggest that central administration of orexin A produces a more robust effect in inducing food intake than peripheral administration. Edwards et al. (1999), Sakurai et al. (1998), Shiraishi et al. (2000), Takano et al. (2004) and Yamanaka et al. (2000) Sprague-Dawley rats Male Increased food intake Espana et al. (2002), Ford et al. (2005), Haynes et al. (1999), Karasawa et al. (2014), Kokare et al. (2006), Li et al. (2015), Monda et al. (2003), Moreno et al. (2005), Sahu, (2002 and Zheng et al. (2005) Wistar rats Male No effect on food intake Ida et al. (1999) and Semjonous et al. (2009) Increased food intake and reduced feeding time Tsuji et al. (2011) Continuous infusion increases daily food intake Yamanaka et al. (1999) Doane et al. (2007), Dube et al. (1999), Kotz et al. (2002), Sweet et al. (1999), Sweet et al. (2004), Thorpe et al. (2003), Thorpe et al. (2006), Thorpe, Teske, et al. (2005) and Wang and Kotz, (2002) Fischer 344 rats Male Increased food intake Kotz et al. (2005) PVN Sprague-Dawley rats Male Increased food intake Dube et al. (1999) No effect on food intake Sweet et al. (1999) While studies using i.c.v. administration have provided insight into the broad involvement of orexins in feeding, studies using sitespecific injections of orexin A have helped determine the precise brain regions involved in feeding behaviour. ...
... Others argue that the orexin effect in promoting food intake may be partly secondary to changes in wakefulness. Yamanaka et al. (1999) showed that increased daytime wakefulness caused by continuous i.c.v infusion of orexin A per se may have resulted in increased food intake (Yamanaka et al. 1999). Thus, it is likely that animals feed more because they are awake, instead of asleep, during the testing period. ...
Orexins are hypothalamic neuropeptides originally discovered to play a role in the regulation of feeding behaviour. The broad connections of orexin neurons to mesocorticolimbic circuitry suggest they may play a role in mediating reward‐related behaviour beyond homeostatic feeding. Here, we review the role of orexin in a variety of eating‐related behaviour, with a focus on reward and motivation, and the neural circuits driving these effects. One emerging finding is the involvement of orexins in hedonic and appetitive behaviour towards palatable food, in addition to their role in homeostatic feeding. This review discusses the brain circuitry and possible mechanisms underlying the role of orexins in these behaviours. Overall, there is a marked bias in the literature towards studies involving male subjects. As such, future work needs to be done to involve female subjects. In summary, orexins play an important role in driving motivation for high salient rewards such as highly palatable food and may serve as the intersection between homeostatic and hedonic feeding.
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... Orexin modulates calorie intake, energy consumption, and sleep; in response to metabolic signals such as peripheral blood glucose, leptin, and ghrelin levels, the neurons that produce orexin and quickly assess the body's nutritional condition [46]. Several studies in rats showed that intracerebroventricular injection of orexin (mainly orexin-A) in pharmacological doses increases food intake [47][48][49][50]. In contrast, in rats, intracerebroventricular injection of orexin receptor antagonists or antibodies decreases food consumption [47][48][49][50]. ...
... Several studies in rats showed that intracerebroventricular injection of orexin (mainly orexin-A) in pharmacological doses increases food intake [47][48][49][50]. In contrast, in rats, intracerebroventricular injection of orexin receptor antagonists or antibodies decreases food consumption [47][48][49][50]. Orexin enhances food-seeking behavior in rats, and eating results in decreased orexin levels and low activity of hypocretinergic neurons [51]. ...
Background: Narcolepsy is a known auto-immune disease that presents mainly in the teenage years with irresistible sleep attacks. Patients with narcolepsy, especially NT1, have been found to have a high prevalence of obesity and other metabolic derangements.
Objectives: This narrative review aimed to address the relationship between narcolepsy and changes in weight and metabolic rate, and discuss potential mechanisms for weight gain and metabolic changes and future research agendas on this topic. This article will provide a balanced, up-to-date critical review of the current literature and delineates areas for future research to understand the pathophysiological metabolic changes in narcolepsy.
Methods: Articles using predefined keywords were searched for in PubMed and Google Scholar databases, with predefined inclusion and exclusion criteria.
Results: Compared to controls, patients with narcolepsy are more likely to be obese and have higher BMIs and waist circumferences. According to recent research, weight gain in narcolepsy patients may be higher during the disease's outset. The precise mechanisms causing this weight gain remain unknown, though. The available information, albeit limited, does not support differences in basal or resting metabolic rates between patients with narcolepsy and controls other than during the time of disease onset. The evidence supporting a role of orexin in weight gain in humans with narcolepsy is still controversial in the literature. Furthermore, the available data did not show any appreciable alterations in the levels of CSF melanin-concentrating hormone, plasma and CSF leptin, or serum growth hormone in relation to weight gain. Other mechanisms have been proposed, including a reduction in sympathetic tone, hormonal changes, changes in eating behavior and physical activity, and genetic predisposition.
Conclusions: The association between increased body mass index and narcolepsy is well-recognized; however, the relationship between narcolepsy and other metabolic measures, such as body fat/muscle distribution and metabolic rate independent of BMI, is not well documented, and the available evidence is inconsistent. Future longitudinal studies with larger sample sizes are needed to assess BMR in patients with narcolepsy under a standard protocol at the outset of narcolepsy, with regular follow-up.
... This was suggested following two major studies: (i) the hypothalamic expression of orexin precursor was increased during fasting (19,37) and (ii) the pharmacological central administration of orexin in rats induced food intake (food consumption being dependent of the orexin injected dose) (19,(38)(39)(40). This feeding-promoting effect is not as robust as the one induced by NPY and AgRP, but it is considered as similar as the one initiated by MCH and GAL (38,(40)(41)(42)(43)(44)(45). Although the precise effect of OX-B on feeding remains unclear, its orexigenic potential was described to be less potent than OX-A (38,(41)(42)(43)(44)(45)(46), which could be explained by differences in their secondary structures: OX-A being maintained by two disulphide bonds conferring resistance to peptidase actions (20). ...
... This feeding-promoting effect is not as robust as the one induced by NPY and AgRP, but it is considered as similar as the one initiated by MCH and GAL (38,(40)(41)(42)(43)(44)(45). Although the precise effect of OX-B on feeding remains unclear, its orexigenic potential was described to be less potent than OX-A (38,(41)(42)(43)(44)(45)(46), which could be explained by differences in their secondary structures: OX-A being maintained by two disulphide bonds conferring resistance to peptidase actions (20). ...
Originally described to be involved in feeding regulation, orexins/hypocretins are now also considered as major regulatory actors of numerous biological processes, such as pain, sleep, cardiovascular function, neuroendocrine regulation, and energy expenditure. Therefore, they constitute one of the most pleiotropic families of hypothalamic neuropeptides. Although their orexigenic effect is well documented, orexins/hypocretins also exert central effects on energy expenditure, notably on the brown adipose tissue (BAT) thermogenesis. A better comprehension of the underlying mechanisms and potential interactions with other hypothalamic molecular pathways involved in the modulation of food intake and thermogenesis, such as AMP-activated protein kinase (AMPK) and endoplasmic reticulum (ER) stress, is essential to determine the exact implication and pathophysiological relevance of orexins/hypocretins on the control of energy balance. Here, we will review the actions of orexins on energy balance, with special focus on feeding and brown fat function.
... Furthermore, OXA is well-established for its actions on both short-and long-term energy homeostasis. In rodents, both acute and chronic central administration of OXA induces feeding (14)(15)(16)(17). In humans, CSF OXA correlated negatively with body weight, but did not relate to body adiposity (18). ...
... Intra-cerebroventricular injection of OXA induces feeding in rodents (14)(15)(16). Similarly, chronic administration of OXA affects feeding in rats (16,17). Blocking OXA-mediated functions with intra-peritoneally applied OX1R antagonist or intra-cisternally applied OXA antibody resulted in reduced food intake in fasted rats (42,43). ...
Orexin-A (OXA) has been originally isolated from a precursor peptide prepro-orexin from the lateral hypothalamus. The orexin system has been attributed to important functions in sleep, arousal and regulation of energy homeostasis. In addition to its high levels in cerebrospinal fluid, OXA is present in blood. However, reported peptide concentrations in plasma vary significantly depending on the method used. Therefore, a specific and sensitive OXA radioimmunoassay (RIA) with solid phase extraction method was developed to determine whether plasma OXA concentrations is affected by acute feeding and/or wake and sleep in young healthy males. Blood samples were collected for 24 h from nine healthy males (aged 20–24 years; BMI 20.7–26.5) every 2 h starting at 11 a.m. Food was served at 12 p.m, 5:30 p.m, 8 p.m and 8 a.m and the sleep time was between 10 p.m and 7 a.m. Plasma samples were analyzed in addition for cortisol and melatonin levels. Blood pressure was monitored through the experimental period. OXA antibody was raised in rabbits. OXA antiserum had only minor cross-reactivity with prepro-orexin precursor (<0.001%), amino-terminal peptide (<0.001%), carboxy-terminal peptide (0.001%), and orexin-B (0.3%) with high sensitivity (0.15 pg/tube). Plasma OXA levels varied between 0.5 and 16 pg/ml in seven subjects and were undetectable (below 0.5 pg/ml) in two subjects. The OXA concentrations did not correlate to feeding nor wake/sleep, whereas cortisol, melatonin and mean arterial blood pressure presented a clear circadian rhythm in each subject. In conclusion, OXA is present in blood in low amounts and its levels do not follow autonomic nor neuroendocrine circadian rhythms. Thereby, studies examining regulatory mechanisms and influences of OXA from blood samples should interpret results very cautiously.
... Several studies have demonstrated the role of the hypothalamic orexin system in the regulation of food intake. Central administration of OxA produces food consumption, preferentially consumption of high-fat food (10,(13)(14)(15), which in turn activates dopaminergic neurons in the ventral tegmental area (VTA) and orexin neurons in the lateral hypothalamic area (16). Moreover, OxA is implicated in food-seeking motivated by hunger (17) or by Pavlovian cues (18)(19)(20). ...
... Our results are also consistent with reports that intracerebral administration of OxA induces feeding and increases the consumption of high-fat diet (10,(13)(14)(15). Orexin also promotes food seeking motivated by hunger (17) and by Pavlovian cues (18)(19)(20). ...
Orexin neurons originate in the lateral and dorsomedial hypothalamus and perifornical area and produce two different neuropeptides: orexin A (OxA) and orexin B (OxB), which activate OxR1 and OxR2 receptors. In the lateral hypothalamus (LH) orexin neurons are involved in behavior motivated by natural rewards such as palatable food (sugar, high-fat food) and it has been demonstrated similarly that the orexin signaling in the ventral tegmental area (VTA) is implicated in the intake of high-fat food. The VTA is an important area involved in reward processing. Given the involvement of nucleus accumbens (NAc) shell dopamine (DA) in motivation for food, we intended to investigate the effect of OxA on the basal and feeding-activated DA transmission in the NAc shell. OxA is a large peptide and does not cross the blood–brain barrier and for this reason was loaded on two kinds of liposomes: anti-transferrin-monoclonal antibodies (OX26-mAb) and lactoferrin-modified stealth liposomes. The effect of IV administration of both OxA liposomes on NAc shell DA was studied by microdialysis in freely moving rats. OxA, administered using both kinds of liposomes, produced a delayed and transitory increase in dialysate DA in the NAc shell, strongly and lastingly potentiated the increase in dialysate DA elicited by sucrose pellet consumption and increased the number of eaten pellets. These effects of OxA on DA transmission and feeding were prevented by the OxR1 antagonist SB 334867. Hence, OxA acting on VTA OxR1 can facilitate sucrose-stimulated NAc shell DA transmission directly by increasing the basal activity of VTA DA neurons that send their projections to the NAc shell.
... Intra-cerebroventricular injections of orexin A into the PVN, DMH, lateral hypothalamus or the perifornical area stimulates food intake but into the arcuate nucleus or VMH do not. It has been reported that chronic infusion of orexin A increases daytime food intake, and suppresses it during the night phase, which may be a circadian effect of the orexin (Yamanaka et al., 1999). Chronic central administration of orexin A does not significantly change food intake over a 24 h period and body weight in rats, but it transiently increases NPY expression in the arcuate nucleus of rat hypothalamus, suggesting hyperphagia induced by orexins may be mediated NPY (Yamanaka et al., 1999;Lopez et al., 2002). ...
... It has been reported that chronic infusion of orexin A increases daytime food intake, and suppresses it during the night phase, which may be a circadian effect of the orexin (Yamanaka et al., 1999). Chronic central administration of orexin A does not significantly change food intake over a 24 h period and body weight in rats, but it transiently increases NPY expression in the arcuate nucleus of rat hypothalamus, suggesting hyperphagia induced by orexins may be mediated NPY (Yamanaka et al., 1999;Lopez et al., 2002). Prepro-orexin gene expression in the lateral hypothalamus is upregulated by fasting and hypoglycaemia, and it is downregulated by leptin (Cai et al., 1999). ...
Obesity is one of the most important public health problems in the world. It is a medical condition with a chronic imbalance between energy intake and energy expenditure. The prevalence of overweight and obesity in adults and children are rapidly rising, and several factors contributing the increased risk of developing obesity are inactivity, overeating, age, give up smoking, ethnicity, secondary obesity and inherited predisposition or genetic defects.
The regulation of appetite involves highly complex peripheral and central systems that are processed in the brain. The appetite hormones (hypothalamic orexigenic neuropeptides) play critical roles in the control of food intake and obesity. Understanding the pharmacology and physiology of appetite regulation and investigation of the role of appetite hormones in the regulation of food intake in humans will allow us to find potential therapeutic targets for the treatment of obesity.
Key Concepts
Obesity is a medical condition, with excessed body weight in the form of fat, resulted from the failure of energy homoeostasis.
Many factors cause obesity including inactivity, overeating, higher age, drugs, diseases, ethnicity and inherited predisposition to obesity or specific genetic defects.
Obesity is most prevalent in worldwide, WHO predicted that they would rise up to 2.3 billion overweight and 700 million obese in 2015.
Obesity predisposes some chronic diseases as type 2 diabetes, cardiovascular diseases and various cancers or shortens life duration and increases mortality rates.
Neural and humoral signals regulate appetite in brain. The appetite hormones control food intake and energy expenditure, whereas a chronic imbalance in those hormones causes obesity.
... The REV-ERBs and orexin signaling regulate various aspects of food intake [23,57,59,60], energy expenditure [23,52,58,[60][61][62][63][64][65], and sleep [33,35,36,51,[53][54][55][56]. Orexinergic genes are expressed in a circadian manner [40] and the REV-ERBs have been shown to be critical regulators of the circadian rhythm [66]. ...
... The REV-ERBs and orexin signaling regulate various aspects of food intake [23,57,59,60], energy expenditure [23,52,58,[60][61][62][63][64][65], and sleep [33,35,36,51,[53][54][55][56]. Orexinergic genes are expressed in a circadian manner [40] and the REV-ERBs have been shown to be critical regulators of the circadian rhythm [66]. ...
The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression.
... The REV-ERBs and orexin signaling regulate various aspects of food intake [23,57,59,60], energy expenditure [23,52,58,[60][61][62][63][64][65], and sleep [33,35,36,51,[53][54][55][56]. Orexinergic genes are expressed in a circadian manner [40] and the REV-ERBs have been shown to be critical regulators of the circadian rhythm [66]. ...
... The REV-ERBs and orexin signaling regulate various aspects of food intake [23,57,59,60], energy expenditure [23,52,58,[60][61][62][63][64][65], and sleep [33,35,36,51,[53][54][55][56]. Orexinergic genes are expressed in a circadian manner [40] and the REV-ERBs have been shown to be critical regulators of the circadian rhythm [66]. ...
The nuclear receptors REV-ERBα and REV-ERBβ are transcription factors that play pivotal roles in the regulation of the circadian rhythm and various metabolic processes. The circadian rhythm is an endogenous mechanism, which generates entrainable biological changes that follow a 24-hour period. It regulates a number of physiological processes, including sleep/wakeful cycles and feeding behaviors. We recently demonstrated that REV-ERB-specific small molecules affect sleep and anxiety. The orexinergic system also plays a significant role in mammalian physiology and behavior, including the regulation of sleep and food intake. Importantly, orexin genes are expressed in a circadian manner. Given these overlaps in function and circadian expression, we wanted to determine whether the REV-ERBs might regulate orexin. We found that acute in vivo modulation of REV-ERB activity, with the REV-ERB-specific synthetic ligand SR9009, affects the circadian expression of orexinergic genes in mice. Long term dosing with SR9009 also suppresses orexinergic gene expression in mice. Finally, REV-ERBβ-deficient mice present with increased orexinergic transcripts. These data suggest that the REV-ERBs may be involved in the repression of orexinergic gene expression.
... Furthermore, the same study showed that hypothalamic expression of pre-proorexin mRNA is upregulated by fasting (6). Stimulation of appetite by orexins in rats was confirmed in others who found that chronic administration of orexin A promotes food intake but does not affect body weight (11). Studies focused on mechanisms by which orexins may promote appetite in rats found that these effects may be mediated through neuropeptide Y (NPY) signaling (12,13). ...
Orexins A (OXA) and B (OXB) (hypocretin 1 and 2) are neuropeptides produced in the brain and peripheral tissues. Biological activities of orexins are mediated through activation of two G-protein coupled receptors termed as orexin 1 receptor (OX1R) and orexin 2 receptor (OX1R). Orexin system (OXA, OXB, OX1R, OX2R) was implicated in controlling sleep, energy expenditure, appetite, reproduction as well as metabolism and energy homeostasis. In this review, we summarize the current knowledge regarding the role of the orexin system in controlling porcine physiology. Particularly, we review and discuss evidence indicating that in pig and other living organisms, orexins and their receptors modulate the energy homeostasis, reproduction as well as functions of peripheral tissues including the pancreas, adrenal glands, gastro-intestinal tract and adipose tissue.
... Interestingly, in adult rats, the orexigenic activity of OXA followed a circadian pattern, when the intracerebroventricular (icv) injection of OXA stimulated appetite during the light phase, versus an anorexigenic activity during the dark phase [156]. Increased wakefulness as a response to fasting might also be mediated by stimulation of the orexigenic systems [157]. Surprisingly, in mice, the ablation of orexigenic neurons resulted in hypophagia, but late-onset obesity was noticed [158]. ...
The history of coronaviruses revealed that these viruses caused multiple outbreaks in the past, including a previous severe acute respiratory syndrome (SARS) outbreak in 2003. In 2019, a novel SARS virus, SARS-CoV-2, started a drastic pandemic that, up till now, keeps peaking in successive waves owing to the mutational ability of the virus versus the short-term immunity against it. Although the angiotensin-converting enzyme 2 (ACE2) is the gate through which the virus gets access to human cells, yet ACE2 is deemed protective in lung injury yielding vasodilator, anti-fibrotic, and anti-inflammatory peptides. The viral-provoked ACE2 downregulation aggravated a subsequent potentially lethal cytokine storm. Both the tumor necrosis factor-alpha (TNF-α) receptor (TNFR), activated by the proinflammatory cytokine, TNF-α, released during coronavirus disease 2019 (COVID-19), and ACE2 are cleaved by tumor necrosis convertase enzyme (TACE) to render respective soluble decoy mediators. Several risk factors were linked to COVID-19 morbidity and neurological affection, including obesity and diabetes mellitus (DM), attributed to ACE2 overexpression in obesity, a low-grade inflammatory state with both obesity and DM, and defective lung reparative machinery, added to low tissue-to-lung ACE2 expression in DM. The ACE2 shedding by SARS-CoV-2 upon its entry into the brain, together with the inflammatory cytokines invading the brain, predispose to such neurological affection. However, ACE2 was not sufficient to justify the occurrence of neurological disorders with COVID-19, owing to its lower brain expression, relative to other tissues. Other mediators should have contributed to such neurological disorders, of which, orexins (OXs) are discussed, owing to multiple functional similarities to ACE2. Eventually, this review highlights such similarities selected according to their possible relevance to COVID-19 symptomatology and pathology. Both ACE2 and OXs confer anti-inflammatory benefits, reduce cerebral endothelial dysfunction, promote neuronal survival and neurogenesis, and add to their therapeutic potentiality in sepsis. Both ACE2 and OXs assist in moderating the stress responses and the stress-activated hypothalamic-pituitary-adrenal axis. Both ACE2 and OXs are affected by obesity and DM. The loss of ACE2 and OXs signaling was suggested in neuro-inflammatory and neurodegenerative diseases. Of interest is the abundance of OXs in the dissemination routes to the brain, namely, the peripheral olfactory and the enteric systems. The presumptive role of OXs as analgesics and antipyretics might add to their favorable profile. Advantageously, the availability of OXs agonists and antagonists makes it applicable to corroborate or abrogate the future utility of targeting the orexigenic system in terms of COVID-19 neurological affection. Elaborative work, exploring in vitro and in vivo models, is recommended to identify or deny such perspective involvement.
... In chronic injection experiments, the bodyweight of animals does not change with OB-Ala treatment. This is perhaps due to the decrease of both A series of studies reported that infusion of OXR agonists in the brain (either by i.c.v. or in specific brain regions) could evoke sympathoexcitatory responses and increase cardiovascular activities [22][23][24] . Enhanced energy expenditure was also observed in mice that received central OX2R agonist infusion [7] . ...
Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.
... Intra-cerebroventricular injections of OxA was shown to increase food intake in rats, while OxB was less effective [96]. However, orexin infusion stimulates feeding during the light period but not at the dark phase and induces no significant increase of the total food intake over 24 h [97]. ...
Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers. The present review suggests that orexins or the orexin neural circuitry represent potential therapeutic targets for the treatment of multiple pathologies related to inflammation including intestinal bowel disease, multiple sclerosis and septic shock, obesity and digestive cancers.
... The orexin system, which is primarily concerned with increased in energy expenditure, can enhance both spontaneous physical activity and food intake when activated. 37,120 While obesity have become pandemic in recent years, some people may be genetically predisposed to obesity. According to reports, orexins may be a crucial brain components that mediate the obesity resistance mechanism. ...
Orexins are hypothalamus-derived neuropeptides with versatile functions. The most explored domains of orexins’ functions are their
influence on the central nervous system (CNS) implicated in the regulation of sleep/wakefulness cycle, food intake behavior, energy
homeostasis, and cognitive processes. Orexins reportedly bear two isoforms, orexin-A (OXA) and orexin-B (OXB), that act via their specific G protein-coupled receptor (GPCR), OX1R and OX2R. These peptides also play vital roles in various other peripheral organs where they regulate metabolism, neuroendocrine functions, blood pressure, as well as reproductive functions. Interestingly orexins also exhibit immuno-regulatory, anti-inflammatory properties and facilitate the mechanism of obesity resistance. Recent research has also shed light on significant role of orexins, in particular orexin A, in regulating reproductive functions in male since the Leydig cells, Sertoli cells, germ cells in various stages of the development, and even the epididymis and penis, manifest the OXA receptor. It will be intriguing to explore the properties of the orexins in reversing obesity, downregulation of inflammatory responses and mediation of male reproductive functions. The present article thus reviews these multitudinous properties of orexins and comprehends the possible connection among the behavioral, metabolic, anti-inflammatory functions of orexins with their roles in male reproduction
... Intriguingly, loss of orexin neurons or orexin receptors observed in narcolepsy leads to obese phenotype. That is because in healthy individuals, orexins not only elicit food intake but promote energy expenditure, which prevents them from developing obesity (Yamanaka et al. 1999;Hara et al. 2001;Funato et al. 2009;Kotz et al. 2012). Orexin neurons are sensitive to diet and short-term HFD alters the balance of synaptic input to these cells (Linehan et al. 2018). ...
Temporal partitioning of daily food intake is crucial for survival and involves the integration of internal circadian states and external influences such as the light–dark cycle and dietary composition. These intrinsic and extrinsic factors are interdependent with misalignment of circadian rhythms promoting body weight gain, while consumption of a calorie‐dense diet elevates the risk of obesity and blunts circadian rhythms. Recently, we defined the circadian properties of the dorsal vagal complex of the brainstem, a structure implicated in the control of food intake and autonomic tone, but whether and how 24 h rhythms in this area are influenced by diet remains unresolved. Here we focused on a key structure of this complex, the nucleus of the solitary tract (NTS). We used a combination of immunohistochemical and electrophysiological approaches together with daily monitoring of body weight and food intake to interrogate how the neuronal rhythms of the NTS are affected by a high‐fat diet. We report that short‐term consumption of a high‐fat diet increases food intake during the day and blunts NTS daily rhythms in neuronal discharge. Additionally, we found that a high‐fat diet dampens NTS responsiveness to metabolic neuropeptides, and decreases orexin immunoreactive fibres in this structure. These alterations occur without prominent body weight gain, suggesting that a high‐fat diet acts initially to reduce activity in the NTS to disinhibit mechanisms that suppress daytime feeding. image
Key points
The dorsal vagal complex of the rodent hindbrain possesses intrinsic circadian timekeeping mechanisms
In particular, the nucleus of the solitary tract (NTS) is a robust circadian oscillator, independent of the master suprachiasmatic clock
Here, we reveal that rat NTS neurons display timed daily rhythms in their neuronal activity and responsiveness to ingestive cues
These daily rhythms are blunted or eliminated by a short‐term high‐fat diet, together with increased consumption of calories during the behaviourally quiescent day
Our results help us better understand the circadian control of satiety by the brainstem and its malfunctioning under a high‐fat diet
... Orexins-Orexin-A (OR-A), Orexin-B (OR-B) are hypocretin neuropeptide ligands secreted majorly from the lateral hypothalamus, also secreted from locus coeruleus, tuberomammillary nucleus, paraventricular nucleus, and raphe nuclei regions of the brain that binds and activates G-protein-coupled receptors (GPCRs), Orexin receptor-type-1 (OX1R) and Orexin receptor-type-2 (OX2R). Orexin receptors mediate multiple molecular signaling mechanisms connected to feeding behavior, circadian rhythm, energy homeostasis, and drug addiction, sleep disorders, depression, dementia, ischemic stroke, and associated with the pathogenesis of AD [115][116][117][118][119]. In AD, the impaired cholinergic pathway alters the sleep-wake cycle with insomnia at night and excess sleep in the day, OR-A increases Aβ42, P-Tau levels in the Cerebro Spinal Fluid (CSF) causes rapid eye movement sleep, orexinergic neurons in the hypothalamus degenerate, and cognitive function deteriorates [120][121][122]. ...
Alzheimer's disease (AD) is one of the most common, severe neurodegenerative brain disorder characterized by the accumulation of amyloid-beta plaques, neurofibrillary tangles in the brain causing neural disintegration, synaptic dysfunction, and neuronal death leading to dementia. Although many US-FDA-approved drugs like Donepezil, Rivastigmine, Galantamine are available in the market, their consumption reduces only the symptoms of the disease but fails in potency to cure the disease. This disease affects many individuals with aging. Combating the disease tends to be very expensive. This review focuses on biochemical mechanisms in the neuron both at normal and AD state with relevance to the tau hypothesis, amyloid hypothesis, the risk factors influencing dementia, oxidative stress, and neuroinflammation altogether integrated with neurodegeneration. A brief survey is carried out on available biomarkers in the diagnosis of the disease, drugs used for the treatment, and the challenges in approaching therapeutic targets in inhibiting the disease pathologies. This review conjointly assesses the demerits with the inefficiency of drugs to reach targets, their side effects, and toxicity. Optimistically, this review directs on the advantageous strategies in using nanotechnology-based drug delivery systems to cross the blood-brain barrier for improving the efficacy of drugs combined with a novel neuronal stem cell therapy approach. Determinately, this review aims at the natural, non-therapeutic healing impact of physical exercise on different model organisms and the effect of safe neuromodulation treatments using repetitive Transcranial Magnetic Stimulation (rTMS), transcranial Electrical Stimulation (tES) in humans to control the disease pathologies prominent in enhancing the synaptic function.
... Intriguingly, loss of orexin neurons or orexin receptors observed in narcolepsy leads to obese phenotype. That is because in healthy individuals orexins not only elicit food intake but promote energy expenditure, which prevents from developing obesity (Yamanaka et al., 1999;Hara et al., 2001;Funato et al., 2009;Kotz et al., 2012). Orexin neurons are sensitive to diet and short-term high-fat diet alters the balance of synaptic input to these cells (Linehan et al., 2018). ...
Temporal partitioning of daily food intake is crucial for survival and involves the integration of internal circadian states and external influences such as the light-dark cycle and the composition of diet. These intrinsic and extrinsic factors are interdependent with misalignment of circadian rhythms promoting body weight gain, while consumption of a calorie dense diet elevates the risk of obesity and blunts circadian rhythms. Since cardiovascular disease, metabolic disorders, and cancer are comorbid with obesity, understanding the relationships between brain activity and diet is of pivotal importance. Recently, we defined for the first time the circadian properties of the dorsal vagal complex of the brainstem, a structure implicated in the control of food intake and autonomic tone, but if and how 24 h rhythms in this area are influenced by diet remains unresolved. Here we focused on a key structure of this complex, the nucleus of the solitary tract, and using a range of approaches, we interrogated how its neuronal and cellular rhythms are affected by high-fat diet. We report that short term consumption of this diet increases food intake during the day and blunts daily rhythms in gene expression and neuronal discharge in the nucleus of the solitary tract. These alterations in this structure occur without prominent body weight gain, suggesting that high-fat diet acts initially to reduce activity in the nucleus of the solitary tract, thereby disinhibiting mechanisms that suppress daytime feeding.
GRAPHICAL ABSTRACT
... Studies have shown that OX1R has higher affinity for orexin-A, and OX2R has equal affinity for orexin-A and orexin-B (Sakurai et al., 1998). Human and animal studies have shown that orexin-A is important in the control of food intake, body weight, and energy expenditure (Lubkin and Stricker-Krongrad, 1998;Yamanaka et al., 1999;Perez-Leighton et al., 2012). Orexinergic neurons send dense projections to many brain regions, including the limbic system Schmitt et al., 2012). ...
Orexin-A is a circulating neuropeptide and neurotransmitter that regulates food intake and gastric motility. The central nucleus of the amygdala (CeA), which regulates feeding behavior and gastric function, expresses the orexin-1 receptor. The aim of this study was to evaluate the effects of microinjection of exogenous orexin-A into the CeA, on food intake and gastric motility, and to explore the mechanisms of these effects. Normal chow and high fat food (HFF) intake were measured, gastric motility and gastric emptying were evaluated, extracellular single unit firing was recorded, and c-fos expression was determined. The results showed that microinjection of orexin-A into the CeA resulted in increased HFF intake but did not affect normal chow intake. This effect was blocked by an orexin-1 receptor antagonist-SB-334867 and was partially blocked by a dopamine D1 receptor antagonist-SCH-23390. Gastric motility and gastric emptying were enhanced by orexin-A, and the former effect was abolished by subdiaphragmatic vagotomy. The firing frequency of gastric distention-related neurons was regulated by orexin-A via the orexin-1 receptor. Furthermore, c-fos expression was increased in the ventral tegmental area (VTA) and the nucleus accumbens (NAc), the lateral hypothalamus (LHA), and the dorsal motor nucleus of the vagus (DMV) in response to microinjection of orexin-A into the CeA. These findings showed that orexin-A regulated palatable food intake and gastric motility via the CeA. The LHA, the VTA, and the NAc may participate in palatable food intake and the CeA-DMV-vagus-stomach pathway may be involved in regulating gastric motility through the regulation of neuronal activity in the CeA.
... Markedly, SeNPs-CM was actually the main Se supplement, in consideration of the extremely low Se content of the feed (<0.1 μg Se g −1 diet) and the estimable daily intake of adult Wistar rats (about 20-30 g diet day −1 each). [41][42][43] Additionally, visible difference in Se levels was found between M-Se and BCM (P < 0.05). It was the SeNPs within SeNPs-CM contributed to the improvement of Se retention. ...
Background:
Selenium (Se) is an indispensable trace element required for animals and human beings, whereas Se-deficiency can accelerate the development of acute gastric injury induced by over-consumption of alcohol. Selenium nanoparticles (SeNPs), as a special Se-supplement with favorable properties and unique bioactivities, are expected to play a passive role in gastroprotection. To the best of our knowledge, the gastroprotective potential of SeNPs is unknown and also, a rapid preparation of orally stable SeNPs available for prospective commercial application in the clinic is needed. Thus, SeNPs-embedded chitosan microspheres (SeNPs-CM) were developed to deliver SeNPs, and their gastroprotective potential was evaluated.
Results:
Herein, a rapid, eco-friendly and economic preparation process, composed of synthesis of SeNPs decorated by chitosan (CS), purification of CS-SeNPs by ultra-filtration (UF) and spray-drying of the purified CS-SeNPs, was introduced to prepare SeNPs-CM. The uniformly distributed SeNPs with a nanosize range of 60 nm were loaded into CS-microspheres, and they could be released from the microspheres in gastric conditions. In addition, SeNPs-CM were safer than selenite in terms of Se dose, with a LD50 of around 8-fold of that of selenite, and it could efficiently enhance the Se retention in Se-deficient Wistar rats. Furthermore, SeNPs-CM pre-treatment might significantly attenuate the ethanol-induced gastric mucosal damage, based on histological evaluation. It might be partly attributed to the systematic antioxidant activities of SeNPs-CM, reflected by the reduction in lipid peroxidation, the augmentation in antioxidant enzymatic activity as well as decreasing aggressive nitric oxides (NO).
Conclusion:
SeNPs-CM could be taken into consideration as a prospective Se-supplement for the oral delivery of SeNPs, with prominent gastroprotective effect against ethanol-induced mucosal injury.
... The hypnotic landscape, dominated by variations on Z drugs (with different formulations and PK features and/or combinations), changed in 1998 with the discovery of orexins (aka hypocretins), two neuropeptides and their 2 receptors and their role in sleep-wake regulation. [8][9][10][11][12][13] By 1999/2001, it was established that orexin neurons, which are exclusively located in the lateral hypothalamus (LH), are absent, and no orexin was detected in the CSF, in patients suffering from type I narcolepsy (narcolepsy with cataplexy). [14][15][16][17][18] In contrast to humans, narcoleptic dogs have a nonfunctional mutated orexin 2 receptor (OX 2 R), which is responsible for the disease. ...
Insomnia and, more generally, lack of sleep are on the rise. Traditionally treated by classical hypnotics, such as benzodiazepines and Z drugs, which both act on the GABAA receptor, and other modalities, including nondrug therapies, such as cognitive behavioural therapy, there is a range of new hypnotics which are being developed or have recently received market approval. Suvorexant and the like target the orexin/hypocretin system: they should have less side effects in terms of drug–drug interactions with e.g. alcohol, less memory impairment and dependence potential compared to classical hypnotics.
... The word 'orexin' is adapted from the Greek word referring to 'appetite'. Activation of the orexin system can increase both spontaneous physical activity and food intake, and its primary function is to promote an increase in energy expenditure [42,43]. While obesity and overweight have turned pandemic over recent years, there are individuals who may naturally resist obesity. ...
Orexins (or hypocretins) are hypothalamic neuropeptides with a multitude of physiological functions. They occur in two known forms, namely, orexin A and orexin B with a common precursor, preproorexin. The orexin receptors (orexin 1R and orexin 2R) belong to the Family of G-protein coupled receptors. The primary function of the orexin system, i.e. the orexins, their receptors and associated neuronal circuitries, perhaps is to increase spontaneous physical activity and food intake, thereby promoting an increase in energy expenditure. Reports suggest that orexins may be the key brain components to mediate the mechanism of obesity resistance. Recent research also has thrown lights upon a significant role of orexins, especially orexin A, in regulation of male reproductive functions owing to their receptor expressions in vital testicular cells, such as Leydig cells, Sertoli cells as well as spermatozoa at different developmental stages, even in the epididymis and penis. Moreover, orexins have been reported to greatly influence gonadotropin-releasing hormone neurons and their secretions to regulate reproductive functions via modulation of the hypothalamic-pituitary-gonadal axis. Evidence thus implicates participation of orexins in steroidogenesis, spermatogenesis, transportation and maturation of sperm as well as in the control of penile function. However, further research is required in this direction to elucidate the mechanisms by which orexins play a role in different testicular functions and effect of orexins on semen quality.
... In addition, although orexin was originally identified as an orexigenic peptide (Sakurai et al., 1998), the effect is acute and recognized during the light phase. Long-term injection of orexin did not change food intake (Yamanaka et al., 1999), and dual orexin receptor agonist did not alter food intake (Tsuneki et al., 2016). Consistently, we observed similar food intake between wild-type and orexin-deficient mice. ...
Orexins are hypothalamic neuropeptides that regulate feeding, energy expenditure, and sleep. Although orexin-deficient mice are susceptible to obesity, little is known about the roles of the orexin receptors in long-term energy metabolism. Here, we performed the metabolic characterization of orexin receptor-deficient mice. Ox1r-deficient mice were resistant to diet-induced obesity, and their food intake was similar between chow and high-fat food. Ox2r-deficient mice exhibited less energy expenditure than wild-type mice when fed a high-fat diet. Neither Ox1r-deficient nor Ox2r-deficient mice showed body weight gain similar to orexin-deficient mice. Although the presence of a running wheel suppressed diet-induced obesity in wild-type mice, the effect was weaker in orexin neuron-ablated mice. Finally, we did not detect abnormalities in brown adipose tissues of orexin-deficient mice. Thus, each orexin receptor signaling has a unique role in energy metabolism, and orexin neurons are involved in the interactive effect of diet and exercise on body weight gain.
... The possibility of a central action of CCK-8 was considered, since CCK-8 has been reported to activate orexin/hypocretin neurons through CCK1 (CCKA) receptors (55). Orexins have been implicated in regulating sleep/wakefulness and increases in food intake and locomotor activity when administered centrally to animals (56)(57)(58). Conflicting studies have reported that CCK suppressed food intake (59-61) as well as locomotor activity (62) when administered i.p. or intracerebroventricularly, making it difficult to define the central contribution. ...
The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca2+-activated chloride (Cl-) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current. Its expression is reduced, as is CCK current activity in obese mice on a high-fat diet (HFD). Reduced expression of TMEM16B in the heterozygote KO of the channel in sensory neurons results in an obese phenotype with a loss of CCK sensitivity in intestinal nodose neurons, a loss of CCK-induced satiety, and metabolic changes, including decreased energy expenditure. The effect on energy expenditure is further supported by evidence in rats showing that CCK enhances sympathetic nerve activity and thermogenesis in brown adipose tissue, and these effects are abrogated by a HFD and vagotomy. Our findings reveal that Ano2/TMEM16B is a Ca2+-activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity.
... Oreksinin kısa sürelimi yoksa uzun süreli mi yiyecek alımını uyardığını incelemek için Yamanaka ve ark.(23), yedi gün boyunca ratlara oreksin enjeksiyonu uygulamış ve çalışma sonucunda kısa süreli oreksin enjeksiyonunun uzun süreli enjeksiyona göre ratlarda günlük yiyecek alımını daha çok arttırdığını saptamıştır. Benzer bir diğer çalışmada 3 ve 6 saat süreyle oreksin-A enjeksiyonu uygulanan ratlarda yiyecek alımının arttığı, sekiz gün enjeksiyon yapıldığında ise sadece 2'inci ve 6'ıncı günlerde etkisi olduğu, gece beslenmesinin ise azaldığı belirtilmiştir(28). ...
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.
... Orexin-A (OA; hypocretin-1) and orexin-B (OB; hypocretin-2) are closely related small peptides that are widely distributed throughout the central and peripheral nervous systems (de Lecea et al., 1998;Sakurai et al., 1998). Orexins stimulate food intake upon intracerebroventricular administration, and were originally described as regulators of feeding behavior (Yamanaka et al., 1999). Subsequent experiments revealed many other important physiological functions of these peptides, including regulation of the sleep-wake cycle (de Lecea and Sutcliffe, 2005;Chow and Cao, 2016), energy homeostasis (Tsuneki et al., 2012), neuroendocrine functions (Inutsuka and Yamanaka, 2013), glucose metabolism (Tsuneki et al., 2016), stress-adaptive responses (Xiao et al., 2013) and reward-seeking and drug addiction . ...
Orexins, also known as hypocretins, are two neuropeptides secreted from orexin-containing neurons, mainly in the lateral hypothalamus (LH). Orexins orchestrate their effects by binding and activating two G-protein–coupled receptors (GPCRs), orexin receptor type 1 (OX1R) and type 2 (OX2R). Orexin/receptor pathways play vital regulatory roles in many physiological processes, especially feeding behavior, sleep–wake rhythm, reward and addiction and energy balance. Furthermore several reports showed that orexin/receptor pathways are involved in pathological processes of neurological diseases such as narcolepsy, depression, ischemic stroke, drug addiction and Alzheimer’s disease (AD). This review article summarizes the expression patterns, physiological functions and potential molecular mechanisms of the orexin/receptor system in neurological diseases, providing an overall framework for considering these pathways from the standpoints of basic research and clinical treatment of neurological diseases.
... Optogenetic activation of orexin neurons is sufficient to drive wakening from sleep (Adamantids et al. 2007) and the effect of the orexins on food intake is influenced by the time of day (Yamanaka et al. 1999). Therefore, it is likely that the contribution of the orexins to LH-mediated feeding and reward-seeking behaviour are secondary to the regulation of arousal (Berthoud & Münzberg 2011). ...
Emerging evidence from human imaging studies suggests that obese individuals have altered connectivity between the hypothalamus, the key brain region controlling energy homeostasis, and cortical regions involved in decision making and reward processing. Historically, animal studies have demonstrated that the lateral hypothalamus is the key hypothalamic region involved in feeding and reward. The lateral hypothalamus is a heterogeneous structure comprised of several distinct types of neurons which are scattered throughout. In addition, the lateral hypothalamus receives inputs from a number of cortical brain regions suggesting it's uniquely positioned to be a key integrator of cortical information and metabolic feedback. In this review, we summarize how human brain imaging can inform detailed animal studies to investigate neural pathways connecting cortical regions and the hypothalamus. Here, we discuss key cortical brain regions that are reciprocally connected to the lateral hypothalamus and are implicated in decision making processes surrounding food.
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... One month later, in February 1998, a group led by M. Yanagisawa (Howard Hughes Medical Institutes/Dallas) reported the deorphanization of two G-protein-coupled receptors (GPCRs): these were named OX 1 R and OX 2 R and their endogenous ligands named orexin A and B [3]. The name orexin, from the Greek "orexis" for appetite, was related to the observation that when orexins were applied intracerebroventricularly, food intake was increased [5][6][7]. Orexins were also produced exclusively by LH cells, and their sequence identical to that of HCRT1 and HCRT2, respectively; being, as they were, the same peptides as hypocretins. ...
Purpose of Review
This paper focuses on the role of orexin receptors in sleep as evidenced in recent preclinical and clinical work. Orexin A and B and their two receptors (OX1R and OX2R) play essential roles in arousal and sleep/wake regulation, addiction, and stress. The absence of orexin producing cells in the lateral hypothalamus or of orexins in the CSF results in narcolepsy with cataplexy in humans. This finding and others on sleep phenotypes in orexin or orexin receptor knockout mice have triggered drug discovery programs on orexin receptor (OXR) antagonists for the treatment of insomnia and other disorders.
Recent Findings
Several OXR antagonists, most of which are dual OX1R/OX2R antagonists (dual orexin receptor antagonists (DORAs)), have now reached phase II/III clinical trials. Suvorexant (Belsomra®), recently registered in Japan, USA, and Australia for insomnia, is the first orexinergic hypnotic principle of this new class. DORAs promote sleep primarily by increasing REM sleep, with little effect on slow wave sleep (SWS). Based on rodent studies, it is clear that the OX2R is the primary target mediating sleep promotion by DORAs. We briefly review preclinical and clinical data of OXR antagonists in situations of unperturbed and perturbed sleep, e.g., insomnia and various neurological diseases.
Summary
We propose that REM sleep enhancement by DORAs may provide opportunities to treat specific neurological disorders. By contrast, OX2R antagonists such as seltorexant (JNJ-54717793/MIN-202) or MK-1064 may have broader applications as they appear to promote balanced sleep architecture in preclinical models and should, in theory, have a lower narcoleptic/cataplectic potential. These concepts require further validation as more OXR antagonists move beyond early stages of clinical development.
... Chronic i.c.v. OX-A increases intake of normal food, but without increasing bodyweight ( Yamanaka et al., 1999) due to a compensatory reduction in feeding after OX-A manip- ulation ( Ida et al., 1999). However, administration of OX-A directly into the third ventricle specifically facilitates increases in intake of a high fat (41% kcal), high sugar (45% kcal) food (Clegg et al., 2002), but not a low fat diet (11% fat, 75% carbohydrate kcal), and promotes sucrose intake ( Benoit et al., 2005). ...
The orexins are widely regarded potential therapeutic targets for a range of disorders of appetitive motivation, including obesity. The motivational activator theory, the first coherent account of the orexin system's role in appetitive motivation, predicts that orexin release motivates appetitive behaviour when the reinforcer is highly salient, available under a high unit-cost or when reward seeking is cue-driven. The present study tested the effect of intracerebroventricular (i.c.v.) administration of the highly potent and commercially available dual orexin receptor antagonist, TCS 1102, on self-administration and reinstatement of palatable food seeking in hungry and sated rats. TCS 1102 was also tested on FR1, FR5, FR10 and PR schedules. Orexin neuron activation was measured by c-Fos/orexin-A immunohistochemistry after cue-induced reinstatement, an extinction test, or a home-cage control. No effect of i.c.v. TCS 1102 was observed on self-administration at any fixed or progressive ratio schedule of reinforcement or reinstatement in hungry or sated rats. Although there was robust recruitment of orexin neurons during behavioural testing conditions, there was no specific activation of these neurons during cue-induced reinstatement when compared to extinction testing conditions. These results suggest that orexin antagonism may not be a useful therapeutic target for obesity as it does not appear to regulate food-seeking, and that the conditions determining orexin involvement as a motivational activator may be less clear than currently understood.
... Similarly, in orexin-deficient mice, in addition to sleep/arousal cycle abnormalities, a lower level of spontaneous physical activity and obesity (regardless of hypophagia) have been described (Hara et al., 2001). Despite an orexigenic effect of acute orexin treatment, chronic icv orexin-A infusion does not lead to weight gain (Yamanaka et al., 1999). Moreover, recent findings reveal that orexin cells activity decreases after eating onset and their silencing leads to eating facilitation (González et al., 2016), which is in line with the obesity observed in orexin-deficient mice (Hara et al., 2001). ...
Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the “control” of the “master biological clock” reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements.
... After 6 weeks, the weight of orexin-A injected mice was not significantly different from the weight of control mice, which is in agreement with previous studies showing that chronic i.c.v. injections do not result in body weight gain [36]. However, we observed a small but significant reduction of visceral fat mass and adiposity but we did not observe any decrease of the subcutaneous fat, suggesting a lesser sensitivity of these fat pads to orexin-A. ...
Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking and drug addiction. Orexin-A treatment was also shown to reduce tumor development in xenografted nude mice and is thus a potential treatment for carcinogenesis. The aim of this work was to explore in healthy mice the consequences on energy expenditure components of an orexin-A treatment at a dose previously shown to be efficient to reduce tumor development. Physiological approaches were used to evaluate the effect of orexin-A on food intake pattern, energy metabolism body weight and body adiposity. Modulation of the expression of brain neuropeptides and receptors including NPY, POMC, AgRP, cocaine- and amphetamine related transcript (CART), corticotropin-releasing hormone (CRH) and prepro-orexin (HCRT), and Y2 and Y5 neuropeptide Y, MC4 (melanocortin), OX1 and OX2 orexin receptors (Y2R, Y5R, MC4R, OX1R and OX2R, respectively) was also explored. Our results show that orexin-A treatment does not significantly affect the components of energy expenditure, and glucose metabolism but reduces intraperitoneal fat deposit, adiposity and the expression of several brain neuropeptide receptors suggesting that peripheral orexin-A was able to reach the central nervous system. These findings establish that orexin-A treatment which is known for its activity as an inducer of tumor cell death, do have minor parallel consequence on energy homeostasis control.
... Orexin has an important role in orchestrating multiple behavioral and physiological functions. (Chemelli et al., 1999;Nambu et al., 1999;Samson et al., 1999;Yamanaka et al., 1999;Chen et al., 2000;Antunes et al., 2001;Hara et al., 2001;Willie et al., 2001;Machado et al., 2002;Sakurai, 2007;Kuwaki, 2008Kuwaki, , 2015Tsujino and Sakurai, 2009;Inutsuka et al., 2014;Mahler et al., 2014;Sakurai, 2014;Bonnavion et al., 2015;Kuwaki, 2015). In mice this role has been investigated by experiments using prepro-orexin knockout (ORX-KO) animals that cannot produce orexin. ...
Our series of rat experiments have shown that locomotor activity, arousal level, body and brown adipose tissue temperatures, heart rate and arterial pressure increase episodically in an integrated manner approximately every 100 min (ultradian manner). Although it has been proposed that the integrated ultradian pattern is a fundamental biological rhythm across species, there are no reports of the integrated ultradian pattern in species other than rats. The aim of the present study was to establish a mice model using simultaneous recording of locomotor activity, eating behaviour, body temperature, heart rate and arousal in order to determine whether their behaviour and physiology are organised in an ultradian manner in normal (wild type) mice. We also incorporated the same recording in prepro-orexin knockout mice to reveal the role of orexin in the brain mechanisms underlying ultradian patterning. The orexin system is one of the key conductors required for coordinating autonomic functions and behaviours, and thus may contribute to ultradian patterning. In wild type mice, locomotor activity, arousal level, body temperature and heart rate increased episodically every 93±18 min (n=8) during 24 hours. Eating was integrated into the ultradian pattern, commencing 23±4 min (n=8) after the onset of an EEG ultradian episode. The integrated ultradian pattern in wild type mice is very similar to that observed in rats. In prepro-orexin knockout mice, the ultradian episodic changes in locomotor activity, EEG arousal indices and body temperature were significantly attenuated, but the ultradian patterning was preserved. Our findings support the view that the ultradian pattern is common across species. The present results also suggest that orexin contributes to driving ultradian episodic changes, however, this neuropeptide is not essential for the generation of the ultradian pattern.
... After 6 weeks, the weight of orexin-A injected mice was not significantly different from the weight of control mice, which is in agreement with previous studies showing that chronic i.c.v. injections do not result in body weight gain [36]. However, we observed a small but significant reduction of visceral fat mass and adiposity but we did not observe any decrease of the subcutaneous fat, suggesting a lesser sensitivity of these fat pads to orexin-A. ...
Introduction et but de l’étude
Les orexines ou hypocrétines 1 et 2, via la stimulation des récepteurs aux orexines 1 (OX1R) et 2 (OX2R), jouent un rôle non seulement dans la régulation des phases d’éveil et de sommeil, de la prise alimentaire, du contrôle du poids et de la dépense énergétique mais également stimulent l’apoptose des cellules cancéreuses. Voisin et al. (2011) ont montré que les récepteurs OX1R sont spécifiquement exprimés dans les cellules cancéreuses du côlon, les cellules saines adjacentes n’exprimant pas ce récepteur. Ces travaux suggèrent que les orexines pourraient être un traitement prometteur de certains types de cancer. Connaissant l’implication des orexines dans de nombreuses fonctions physiologiques et en particulier dans le contrôle de la prise alimentaire il semblait indispensable de vérifier les conséquences d’un traitement chronique aux orexines sur ces fonctions avant d’envisager une approche thérapeutique.
Matériel et méthodes
Notre étude incluait deux groupes de souris Balb/c qui ont reçu soit des injections avec le véhicule (groupe témoin) ou avec l’orexine A (1 μmole/kg) pendant 6 semaines. Les animaux ont été pesés quotidiennement. Les séquences de prise alimentaires alimentaire ont été étudiées au cours de la dernière semaine par enregistrement sur 24 h et un test de tolérance au glucose a été effectué avant le sacrifice des animaux. À la fin de l’étude les compositions corporelles ont été mesurées par dissection et pesée des principaux organes et dépôts adipeux. L’expression hypothalamique des neuropeptides et des récepteurs a été quantifiée par PCR en temps réel.
Résultats
Nos travaux montrent qu’un traitement chronique avec une dose d’orexine capable d’induire l’apoptose des cellules cancéreuses, est capable de réduire au niveau du cerveau l’expression du récepteur (OX1R) et d’induire une légère diminution du tissu adipeux. Cependant ce traitement n’a pas d’impact sur la prise de poids des animaux, ni sur le métabolisme glucidique. Concernant la prise alimentaire seule la vitesse d’ingestion de la nourriture augmente significativement mais pas la quantité ingérée.
Conclusion
À une concentration efficace pour induire l’apoptose des cellules cancéreuses nous n’observons pas de modifications du comportement alimentaire ni de la prise de poids des animaux après 6 semaines de traitement.
... ORX/hcrt neurons are activated in anticipation of feeding, couple arousal and feeding behaviors (Akiyama et al., 2004;Mieda et al., 2004). Interestingly, ORX promotes feeding during the day but not during dark phases (Haynes et al., 1999;Yamanaka et al., 1999;McGregor et al., 2011), indicating that ORX promotes feeding via an increase of arousal. In contrast to ORX/hcrt neurons, MCH neurons are GABAergic and MCH only amplifies consumption (e.g., size and amount; Baird et al., 2006Baird et al., , 2008, suggesting that MCH regulates general consumption behavior, but not necessarily hedonic aspects of feeding (Clegg et al., 2002;Sakamaki et al., 2005). ...
The last two decades of research provided evidence for a substantial heterogeneity among feeding-related neurons (FRNs) in the hypothalamus. However, it remains unclear how FRNs differ in their firing patterns during food intake. Here, we investigated the relationship between the activity of neurons in mouse hypothalamus and their feeding behavior. Using tetrode-based in vivo recording technique, we identified various firing patterns of hypothalamic FRNs, which, after the initiation of food intake, can be sorted into four types: sharp increase (type I), slow increase (type II), sharp decrease (type III) and sustained decrease (type IV) of firing rates. The feeding-related firing response of FRNs was rigidly related to the duration of food intake and, to a less extent, associated with the type of food. The majority of these FRNs responded to glucose and leptin and exhibited electrophysiological characteristics of putative GABAergic neurons. In conclusion, our study demonstrated the diversity of neurons in the complex hypothalamic network coordinating food intake.
... However, when orexin was injected in the cerebral ventricle at the start of the dark period, food intake did not change (Haynes et al. 1999). Moreover, a chronic administration of orexin did not change daily food intake (Haynes et al. 1999;Yamanaka et al. 1999), which suggests that orexin's effects are short-term and apparent during the light period. The pharmacogenetic activation of orexin neurons during the light period increased food intake (Inutsuka et al. 2014), as well as the total wake time (Sasaki et al. 2011). ...
Orexin has been confirmed to exhibit acute orexigenic effects, especially for palatable food. However, the loss of orexin renders mice susceptible to obesity, which suggests that orexin neurons function as a negative regulator of energy metabolism over an extended period of time. Thus, orexin exerts differential short-term and long-term effects on feeding behavior and energy metabolism. Orexin neurons are able to sense nutritional and energy status directly or indirectly through leptin, glucose, amino acids and other factors. Orexin neurons project to various brain regions from the forebrain to the spinal cord, which are involved in food intake, reward behavior and sympathetic nervous system activity; orexin's effects in these regions modulate food salience and energy expenditure. Orexin has also been reported to be involved in glucose and bone metabolism. Surprisingly, very little is currently known regarding the roles of the two orexin receptors and especially regarding the long-term effects on metabolism. The local action of orexin in the peripheral organs remains controversial. © Springer International Publishing Switzerland 2015. All rights reserved.
The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.
Orexin-A (OXA) is a hypothalamic neuropeptide implicated in the regulation of wakefulness, appetite, reward processing, muscle tone, motor activity, and other physiological processes. The broad range of systems affected stems from the widespread projections of orexin neurons toward multiple brain regions regulating numerous physiological processes. Orexin neurons integrate nutritional, energetic, and behavioral cues and modulate the functions of target structures. Orexin promotes spontaneous physical activity (SPA), and we recently showed that orexin injected into the ventrolateral preoptic area (VLPO) of the hypothalamus increases behavioral arousal and SPA in rats. However, the specific mechanisms underlying the role of orexin in physical activity are unknown. Here we tested the hypothesis that OXA injected into the VLPO alters the oscillatory activity in the electroencephalogram (EEG) to reflect an increased excitability of the sensorimotor cortex, which may explain the associated increase in SPA. The results showed that OXA increased wakefulness following injections into the VLPO. In addition, OXA altered the power spectrum of the EEG during the awake state by decreasing the power of 5-19 Hz oscillations and increasing the power of >35 Hz oscillations, which are markers of increased sensorimotor excitability. Consistently, we found that OXA induced greater muscle activity. Furthermore, we found a similar change in power spectrum during slow-wave sleep, which suggests that OXA altered the EEG activity in a fundamental way, even in the absence of physical activity. These results support the idea that OXA increases the excitability of the sensorimotor system, which may explain the corresponding increase in awake time, muscle tone, and SPA.
Orexins are excitatory neuropeptides, which are predominantly associated with feeding behavior, sleep-wake cycle and energy homeostasis. The orexinergic system comprises of HCRTR1 and HCRTR2, G-protein-coupled receptors of rhodopsin family and the endogenous ligands processed from HCRT pro-hormone, Orexin A and Orexin B. These neuropeptides are biosynthesized by the orexin neurons present in the lateral hypothalamus area, with dense projections to other brain regions. The orexin-receptor signaling is implicated in various metabolic as well as neurological disorders, making it a promising target for pharmacological interventions. However, there is limited information available on the collective representation of the signal transduction pathways pertaining to the orexin-orexin receptor signaling system. Here, we depict a compendium of the Orexin A/B stimulated reactions in the form of a basic signaling pathway map. This map catalogs the reactions into five categories: molecular association, activation/inhibition, catalysis, transport, and gene regulation. A total of 318 downstream molecules were annotated adhering to the guidelines of NetPath curation. This pathway map can be utilized for further assessment of signaling events associated with orexin-mediated physiological functions and is freely available on WikiPathways, an open-source pathway database ( https://www.wikipathways.org/index.php/Pathway:WP5094 ).
The orexins, also known as hypocretins, are two neuropeptides (orexin A and B or hypocretin 1 and 2) produced by a few thousand neurons located in the lateral hypothalamus that were independently discovered by two research groups in 1998. Those two peptides bind two receptors (orexin/hypocretin receptor 1 and receptor 2) that are widely distributed in the brain and involved in the central physiological regulation of sleep and wakefulness, orexin receptor 2 having the major role in the maintenance of arousal. They are also implicated in a multiplicity of other functions, such as reward seeking, energy balance, autonomic regulation and emotional behaviours. The destruction of orexin neurons is responsible for the sleep disorder narcolepsy with cataplexy (type 1) in humans, and a defect of orexin signalling also causes a narcoleptic phenotype in several animal species. Orexin discovery is unprecedented in the history of sleep research, and pharmacological manipulations of orexin may have multiple therapeutic applications. Several orexin receptor antagonists were recently developed as new drugs for insomnia, and orexin agonists may be the next‐generation drugs for narcolepsy. Given the broad range of functions of the orexin system, these drugs might also be beneficial for treating various conditions other than sleep disorders in the near future.
Orexin neurons play an important role in stress‐related mental disorders including post‐traumatic stress disorder (PTSD). Anxiety‐ and depression‐related symptoms commonly occur in combination with PTSD. However, the role of the orexin system in mediating alterations in these affective symptoms remains unclear. The medial prefrontal cortex (mPFC) is implicated in both cognitive and emotional processing. In the present study, we investigated anxiety‐ and depression‐related behavioral changes using the elevated plus maze (EPM), the sucrose preference test (SPT), and the open field (OF) test in male rats with single prolonged stress (SPS) induced‐PTSD. The expression of orexin‐A in the hypothalamus and orexin receptors (OX1R and OX2R) in the mPFC was detected and quantified by immunohistochemistry, western blotting, and real‐time polymerase chain reaction (qRT‐PCR). We found that the SPS rats exhibited enhanced levels of anxiety, reduced exploratory activities, and anhedonia. Furthermore, SPS resulted in reductions in the expression of orexin‐A in the hypothalamus and the increased expression of OX1R in the mPFC. The intracerebroventricular administration of orexin‐A alleviated behavioral changes in SPS rats and partly restored the increased levels of OX1R in the mPFC. These results suggest that the orexin system plays a role in the anxiety‐ and depression‐related symptoms observed in PTSD. This article is protected by copyright. All rights reserved. SPS rats exhibited enhanced levels of anxiety, reduced exploratory activities, and anhedonia. SPS reduced the expression levels of orexin‐A in the hypothalamus and increased the expression levels of OX1R in the mPFC. Moreover, the intracerebroventricular administration of orexin‐A alleviated anxiety‐like behaviors, improved the reduction of locomotor activity in SPS rats, and partly restored OX1R levels in the mPFC. Therefore, the orexin system plays a role in the anxiety‐ and depression‐related symptoms observed in PTSD.
Hypocretin-1 and 2 (or orexin A and B) are neuropeptides exclusively produced by a group of neurons in the lateral and dorsomedial hypothalamus that project throughout the brain. In accordance with this, the two different hypocretin receptors are also found throughout the brain. The hypocretin system is mainly involved in sleep–wake regulation, but also in reward mechanisms, food intake and metabolism, autonomic regulation including thermoregulation, and pain.
The disorder most strongly linked to the hypocretin system is the primary sleep disorder narcolepsy type 1 caused by a lack of hypocretin signaling, which is most likely due to an autoimmune process targeting the hypocretin-producing neurons. However, the hypocretin system may also be affected, but to a lesser extent and less specifically, in various other neurological disorders. Examples are neurodegenerative diseases such as Alzheimer’s, Huntington's and Parkinson's disease, immune-mediated disorders such as multiple sclerosis, neuromyelitis optica, and anti-Ma2 encephalitis, and genetic disorders such as type 1 diabetus mellitus and Prader–Willi Syndrome. A partial hypocretin deficiency may contribute to the sleep features of these disorders.
Cerebral ischaemia is accompanied by infectious complications due to immunosuppression, known as stroke-induced immunodepression (SIID). Orexin-A (OXA), a neuropeptide produced in the hypothalamus, has been reported to have neuroprotective properties after stroke and is known to modulate inflammatory processes in peripheral tissues. The aim of this study was to determine the effects of orexin-A (OXA) on cerebral ischaemic inflammatory injury and SIID following experimental stroke. Cerebral ischaemia was induced in C57/BL6 mice by middle cerebral artery occlusion (MCAO). A mouse model of pneumonia and poststroke pneumococcal pneumonia was established by intratracheal inoculation with S. pneumoniae in a normal mouse or MCAO mouse model on the third day. We found that OXA postconditioning inhibited cerebral ischaemic inflammatory injury. The mechanism involved downregulation of the NF-κB signalling pathway. In addition, OXA may serve as a potential treatment target for attenuating stroke-induced immunodepression in mice.
The orexin neuron in lateral hypothalamus (LH) was involved in the regulation of sleep-wake cycle. However, the effect of orexin A (OXA) on cognitive impairment resulting from diverse diseases remains controversial. In this study, we investigated the effect of OXA on cognitive impairment induced by chronic intermittent hypoxia (CIH) in mice. Adult (10 weeks old) male C57BL/6 mice were randomly divided into the following four groups: normoxia control (NC)+normal saline (NS), NC + OXA, CIH + NS and CIH + OXA group. Following the CIH mice models establishment, OXA was injected into the right lateral ventricles of mice by a micro-injection system. Water maze test was used to assess spatial memory abilities of the mice. The expression of OXA and c-Fos in LH were analyzed by immunofluorescence staining. Apoptotic cell death and oxidative stress in hippocampus were evaluated using multiple methods including TUNEL, western blot and biochemical analysis. Behavioral tests revealed that CIH significantly increased the escape latency and time of arriving platform, of which were markedly decreased by OXA treatment. Similarly, the CIH + NS group was worse than NC + NS group in terms of the number of platform crossing and time in the target quadrant, of which were also significantly improved by OXA treatment. The number of OXA + neuron in LH was decreased, but the percentage of c-Fos+/OXA + neuron in LH was remarkably increased by CIH. Furthermore, we found that micro-injection of OXA attenuated CIH-induced apoptotic cell death and oxidative stress in the hippocampus. Our results suggested that OXA might improve cognitive impairment induced by CIH through inhibiting hippocampal apoptosis and oxidative stress.
Medications, at present, play a limited role on eating disorders. Currently, only two drugs were approved by the Food and Drug Administration, fluoxetine and lisdexamfetamine dimesylate, respectively, for bulimia nervosa and binge eating disorder. Meanwhile, eating disorders are a growing public health problem, and the pharmacological management is extremely important, in support of the recommended cognitive behavioral therapy. In this context, animal models are essential to facilitate the study of human conditions and validate potential therapies. In this chapter, we will describe a preclinical model of binge-like eating, triggered by yo-yo dieting and frustration stress on palatable food. It represents a tool to investigate the underlying behavior, physiological mechanisms and the involvement of neural circuitry on binge-like eating behavior with the final aim to develop pharmacological approaches. Corticotropin-releasing factor 1 receptor antagonists, orexin receptor type 1 antagonists, and A2A adenosine receptor agonists will be discussed as promising therapeutic treatments that may have clinical implications.
Understanding how the brain coordinates energy status with the motivation to eat is crucial to identify strategies to improve disordered body weight. The ventral tegmental area (VTA), known as the core of the mesolimbic system, is of particular interest in this regard because it controls the motivation to consume palatable, calorie-dense foods and to engage in volitional activity. The VTA is largely composed of dopamine (DA) neurons, but modulating these DA neurons has been alternately linked with promoting and suppressing feeding, suggesting heterogeneity in their function. Subsets of VTA DA neurons have recently been described based on their anatomical distribution, electrophysiological features, connectivity and molecular expression, but to date there are no signatures to categorize how DA neurons control feeding. Assessing the neuropeptide receptors expressed by VTA DA neurons may be useful in this regard, as many neuropeptides mediate anorexic or orexigenic responses. In particular, the lateral hypothalamic area (LHA) releases a wide variety of feeding-modulating neuropeptides to the VTA. Since VTA neurons intercept LHA neuropeptides known to either evoke or suppress feeding, expression of the cognate neuropeptide receptors within the VTA may point to VTA DA neuronal mechanisms to promote or suppress feeding, respectively. Here we review the role of the VTA in energy balance and the LHA neuropeptide signaling systems that act in the VTA, whose receptors might be used to classify how VTA DA neurons contribute to energy balance
Introduction: It is specified that serum levels of Orexin-A has a negative correlation
with serum levels of glucose. Exercise and diet are the main regulators of blood
circulation of Orexin-A. Therefore, the aim of current study was to investigate the effect
of acute aerobic exercise following four different diets on the levels of Orexin-A and
glucose in overweight men.
Methods: In this quasi-experimental single-blinded crossover study, 10 overweight men
(aged 23± 6.1 and BMI 29.26 ± 0.47), attended the physiology lab for 4 sessions with a
week interval. In each session, two hours after having Normal (N), High carbohydrate
(HCHO), High protein (HP) and High-fat (HF) diets, subjects performed 30 min treadmill
aerobic exercise with 60-70% of maximum heart rate. In each session, three blood
samples were taken in fasting, 2 hours after the diet (before exercise) and after the
exercise.
Results: Serum levels of Orexin-A after acute aerobic exercise following HCHO and HP
diet were significantly higher compared to HF diet (P≤ 0.019 and P≤ 0.033, respectively).
There was no significant difference in serum levels of glucose after aerobic exercise
following 4 different diets (P = 0.072).
Conclusions: The present study demonstrated that in overweight men, calorie intake
especially from HF diet, reduces serum levels of Orexin-A. In addition, acute aerobic
exercise after having HF diet did not change serum levels of Orexin-A. Also, there was
no significant difference in glucose levels as a result of comparing 4 sessions.
Animals must ingest water via drinking to maintain fluid homeostasis, yet the neurons that specifically promote drinking behavior are incompletely characterized. The lateral hypothalamic area (LHA) as a whole is essential for drinking behavior but most LHA neurons indiscriminately promote drinking and feeding. By contrast, activating neurotensin (Nts)-expressing LHA neurons (termed LHA Nts neurons) causes mice to immediately drink water with a delayed suppression of feeding. We therefore hypothesized that LHA Nts neurons are sufficient to induce drinking behavior and that these neurons specifically bias for fluid intake over food intake. To test this hypothesis we used designer receptors exclusively activated by designer drugs (DREADDs) to selectively activate LHA Nts neurons and studied the impact on fluid intake, fluid preference and feeding. Activation of LHA Nts neurons stimulated drinking in water-replete and dehydrated mice, indicating that these neurons are sufficient to promote water intake regardless of homeostatic need. Interestingly, mice with activated LHA Nts neurons drank any fluid that was provided regardless of its palatability, but if given a choice they preferred water or palatable solutions over unpalatable (quinine) or dehydrating (hypertonic saline) solutions. Notably, acute activation of LHA Nts neurons robustly promoted fluid but not food intake. Overall, our study confirms that activation of LHA Nts neurons is sufficient to induce drinking behavior and biases for fluid intake. Hence, LHA Nts neurons may be important targets for orchestrating the appropriate ingestive behavior necessary to maintain fluid homeostasis.
This article is part of the Special Issue entitled ‘Hypothalamic Control of Homeostasis’.
The hypocretins (also called the orexins) are two C-terminally amidated neuropeptides of related sequence. They are produced from a common precursor whose expression is restricted to a few thousand neurons of the rat dorsolateral hypothalamus. Two G‐protein‐coupled receptors (GPCRs) for the hypocretins have been identified, and these have different distributions within the CNS and differential affinities for the two hypocretins. The hypocretins have been detected in secretory vesicles at synapses of fibers that project to areas within the posterior hypothalamus that are implicated in feeding behaviors and hormone secretion. Hypocretin fibers also project to diverse targets in other brain regions and the spinal cord, including several areas implicated in cardiovascular function and sleep–wake regulation. The peptides are excitatory when applied directly in vivo and to cultured neurons and slices, although there is also evidence for some inhibitory signaling. Administration of the hypocretins stimulates food intake, affects blood pressure, hormone secretion, and locomotor activity, and increases wakefulness while suppressing rapid eye movement (REM) sleep. Inactivating mutations in the hypocretin receptor 2 gene (hcrtr 2) in dogs result in narcolepsy. Mice whose hypocretin gene has been inactivated exhibit a narcolepsy‐like phenotype. Most human patients with narcolepsy have greatly reduced levels of hypocretin peptides in their cerebrospinal fluid (CSF) and no or barely detectable hypocretin neurons in their hypothalami, suggestive of autoimmune attack. One aspect of hypocretin activity is the direct excitation of cholinergic forebrain neurons, brainstem monoaminergic REM‐off neurons in the locus coeruleus and dorsal raphe nucleus, and histaminergic tuberomammillary nucleus (TMN), which together suppress slow‐wave sleep. The hypocretins also modulate the activity of cholinergic REM‐on neurons in the brainstem, which gate REM entry. The effects on wakefulness appear to be the dominant activities of the hypocretin system and are twofold: maintenance of the waking state and suppression of REM entry.
The neuropeptide hypocretin is also commonly referred to as orexin, since its orexigenic action was recognized early. Orexin/hypocretin (OX) neurons project widely throughout the brain and the physiologic and behavioral functions of OX are much more complex than initially conceived based upon the stimulation of feeding. OX most notably controls functions relevant to attention, alertness, and motivation. OX also plays multiple crucial roles in the control of food intake, metabolism, and overall energy balance in mammals. OX signaling not only promotes food-seeking behavior upon short-term fasting to increase food intake and defend body weight, but, conversely, OX signaling also supports energy expenditure to protect against obesity. Furthermore, OX modulates the autonomic nervous system to control glucose metabolism, including during the response to hypoglycemia. Consistently, a variety of nutritional cues (including the hormones leptin and ghrelin) and metabolites (e.g., glucose, amino acids) control OX neurons. In this chapter, we review the control of OX neurons by nutritional/metabolic cues, along with our current understanding of the mechanisms by which OX and OX neurons contribute to the control of energy balance and metabolism.
The discovery of the orexin system represents the single major progress in the sleep field of the last three to four decades. The two orexin peptides and their two receptors play a major role in arousal and sleep/wake cycles. Defects in the orexin system lead to narcolepsy with cataplexy in humans and dogs and can be experimentally reproduced in rodents. At least six orexin receptor antagonists have reached Phase II or Phase III clinical trials in insomnia, five of which are dual orexin receptor antagonists (DORAs) that target both OX1 and OX2 receptors (OX2Rs). All clinically tested DORAs induce and maintain sleep: suvorexant, recently registered in the USA and Japan for insomnia, represents the first hypnotic principle that acts in a completely different manner from the current standard medications. It is clear, however, that in the clinic, all DORAs promote sleep primarily by increasing rapid eye movement (REM) and are almost devoid of effects on slow-wave (SWS) sleep. At present, there is no consensus on whether the sole promotion of REM sleep has a negative impact in patients suffering from insomnia. However, sleep onset REM (SOREM), which has been documented with DORAs, is clearly an undesirable effect, especially for narcoleptic patients and also in fragile populations (e.g. elderly patients) where REM-associated loss of muscle tone may promote an elevated risk of falls. Debate thus remains as to the ideal orexin agent to achieve a balanced increase in REM and non-rapid eye movement (NREM) sleep. Here, we review the evidence that an OX2R antagonist should be at least equivalent, or perhaps superior, to a DORA for the treatment of insomnia. An OX2R antagonist may produce more balanced sleep than a DORA. Rodent sleep experiments show that the OX2R is the primary target of orexin receptor antagonists in sleep modulation. Furthermore, an OX2R antagonist should, in theory, have a lower narcoleptic/cataplexic potential. In the clinic, the situation remains equivocal, since OX2R antagonists are in early stages: MK-1064 has completed Phase I, and MIN202 is currently in clinical Phase II/III trials. However, data from insomnia patients have not yet been released. Promotional material suggests that balanced sleep is indeed induced by MIN-202, whereas in volunteers MK-1064 has been reported to act similarly to DORAs.
We determined the immunohistochemical distributions of orexin-A and orexin-B, hypothalamic peptides that function in the regulation
of feeding behavior and energy homeostasis. Orexin-A and -B neurons were restricted to the lateral and posterior hypothalamus,
whereas both orexin-A and -B nerve fibers projected widely into the olfactory bulb, cerebral cortex, thalamus, hypothalamus,
and brainstem. Dense populations of orexin-containing fibers were present in the paraventricular thalamic nucleus, central
gray, raphe nuclei, and locus coeruleus. Moderate numbers of these fibers were found in the olfactory bulb, insular, infralimbic
and prelimbic cortex, amygdala, ventral, and dorsolateral parts of the suprachiasmatic nucleus, paraventricular nucleus except
the lateral magnocellular division, arcuate nucleus, supramammillary nucleus, nucleus of the solitary tract, and dorsal motor
nucleus of the vagus. Small numbers of orexin fibers were present in the perirhinal, motor and sensory cortex, hippocampus,
and supraoptic nucleus, and a very small number in the lateral magnocellular division of the paraventricular nucleus. Intracerebroventricular
injections of orexins induced c-fos expression in the paraventricular thalamic nucleus, locus coeruleus, arcuate nucleus, central gray, raphe nuclei, nucleus
of the solitary tract, dorsal motor nucleus of the vagus, suprachiasmatic nucleus, supraoptic nucleus, and paraventricular
nucleus except the lateral magnocellular division. The unique neuronal distribution of orexins and their functional activation
of neural circuits suggest specific complex roles of the peptides in autonomic and neuroendocrine control.
A new orexigenic peptide called hypocretin (orexin) has recently been described in neurons of the lateral hypothalamus and perifornical area. The medial and lateral hypothalamus have been loosely called satiety and feeding centers of the brain, respectively. Approximately one-third of all medial and lateral hypothalamic neurons tested, but not hippocampal neurons, show a striking nanomolar sensitivity to hypocretin. As studied with calcium digital imaging with fura-2, hypocretin raises cytoplasmic calcium via a mechanism based on G-protein enhancement of calcium influx through plasma membrane channels. The peptide has a potent effect at both presynaptic and postsynaptic receptors. Most synaptic activity in hypothalamic circuits is attributable to axonal release of GABA or glutamate. With whole-cell patch-clamp recording, we show that hypocretin, acting directly at axon terminals, can increase the release of each of these amino acid transmitters. Two hypocretin peptides, hypocretin-1 and hypocretin-2, are coded by a single gene; neurons that respond to one peptide also respond to the other. In addition to its effect on feeding, we find that this peptide also regulates the synaptic activity of physiologically identified neuroendocrine neurons studied in hypothalamic slices containing the arcuate nucleus, suggesting a second function of hypocretin in hormone regulation. The widespread distribution of hypocretin axons, coupled with the strong response to the peptide at both presynaptic and postsynaptic sites, suggests that the peptide probably modulates a variety of hypothalamic regulatory systems and could regulate the axonal input to these regions presynaptically.
Hypocretin (orexin) has recently been shown to increase feeding when injected into the brain. Using both rat and primate brains, we tested the hypothesis that a mechanism of hypocretin action might be related to synaptic regulation of the neuropeptide Y (NPY) system. Hypocretin-immunoreactive terminals originating from the lateral hypothalamus make direct synaptic contact with neurons of the arcuate nucleus that not only express NPY but also contain leptin receptors. In addition, hypocretin-containing neurons also express leptin receptor immunoreactivity. This suggests a potential mechanism of action for hypocretin in the central regulation of metabolic and endocrine processes. The excitatory actions of hypocretin could increase NPY release, resulting in enhanced feeding behavior and altered endocrine regulation, whereas leptin, released from adipose tissue as an indicator of fat stores, would have the opposite effect on the same neurons, leading to a decrease in NPY and NPY-mediated hypothalamic functions. On the other hand, the innervation of hypocretin cells by NPY boutons raises the possibility that NPY may exert an effect on hypothalamic functions, at least in part, via mediation or feedback action on these lateral hypothalamic cells. Our data indicate that a direct interaction between leptin, hypocretin, and NPY exists in the hypothalamus that may contribute to the central regulation of metabolic and endocrine processes in both rodents and primates.
The effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y (NPY), on the behavior of rats was investigated. An immediate increase in face washing activity was observed after injection of orexin A or orexin B, but not NPY. Orexin A had a more potent effect on face washing behavior than orexin B. Grooming and burrowing activities also increased significantly after injection of orexin A, whereas, orexin B significantly increased burrowing and searching behavior. Feeding behavior and food consumption increased dramatically within 10 min of injection of NPY. Although the significant increase in feeding behavior was also observed after injection of orexin A, total food intake did not change significantly. These results suggest that orexin may be involved in the regulation of several other behavioral activities in rats, besides feeding.
Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides which stimulate food intake when administered intracerebroventricularly. Orexins are specifically localized in neurons within and around the lateral hypothalamic area (LHA). Previous electrophysiological studies have demonstrated that some neurons in the LHA are activated by hypoglycemia, and are therefore termed `glucose-sensitive neurons'. In the present study, we examined whether orexin-containing neurons are activated in the hypoglycemic states, using Fos-like immunoreactivity (FLI) as a marker of neuronal activation. We observed that FLI was induced in the LHA by acute insulin treatment. Double staining with anti-Fos and anti-orexin antibodies revealed that up to 33% of the orexin-containing neurons in the LHA also expressed FLI under the hypoglycemic condition. These results suggest that some populations of neurons which contain orexins are activated under hypoglycemic conditions.
Orexin (ORX)-A and -B are recently identified neuropeptides, which are specifically localized in neurons within and around the lateral hypothalamic area (LHA) and dorsomedial hypothalamic nucleus (DMH), the regions classically implicated in feeding behavior. Here, we report a further study of the distribution of ORX-containing neurons in the adult rat brain to provide a general overview of the ORX neuronal system. Immunohistochemical study using anti-ORX antiserum showed ORX-immunoreactive (ir) neurons specifically localized within the hypothalamus, including the perifornical nucleus, LHA, DMH, and posterior hypothalamic area. ORX-ir axons and their varicose terminals showed a widespread distribution throughout the adult rat brain. ORX-ir nerve terminals were observed throughout the hypothalamus, including the arcuate nucleus and paraventricular hypothalamic nucleus, regions implicated in the regulation of feeding behavior. We also observed strong staining of ORX-ir varicose terminals in areas outside the hypothalamus, including the cerebral cortex, medial groups of the thalamus, circumventricular organs (subfornical organ and area postrema), limbic system (hippocampus, amygdala, and indusium griseum), and brain stem (locus coeruleus and raphe nuclei). These results indicate that the ORX system provides a link between the hypothalamus and other brain regions, and that ORX-containing LHA and DMH neurons play important roles in integrating the complex physiology underlying feeding behavior.
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.
1. The frequency of firing was simultaneously recorded from single neurones of the ventromedial nuclei (VMN) and the lateral hypothalamic area (LHA) in urethane anaesthetized rats for many hours. 2. There were circadian changes of VMN and LHA neurone activity. The pattern of this circadian rhythm is as follows: throughout the day LHA neurones show higher activity than that of VMN, as indicated by higher frequency and more fluctuations in their rates of firing. In late afternoon the discharge rate of LHA neurones increases further, showing oscillations of short duration. In the early evening hours LHA neurone activity gradually goes down, as the VMN neurones become active. Throughout the night, VMN neurones are more active than those of LHA, just the opposite of the day period. In early morning hours VMN neurones gradually become quiet, while LHA neurones begin to show activity. 3. Superimposed on the circadian rhythm, at certain periods of the day, VMN and LHA neurones showed short duration oscillations in rate of firing, roughly every 7-15 sec and every 3-5 min. 4. Activities in neurones of the VMN and LHA were reciprocally related; a decrease in firing rate of one was associated with an increase in the other. This phenomenon was shown clearly by analysis of auto- and cross-correlation functions of firing patterns of VMN and LHA neurones. 5. The effects of stimulations of the prefrontal cortex and splanchnic afferents on VMN and LHA neurones depended on the basic firing frequency, thus they varied with the time of day. Definite relationships exist between basic firing frequency of a cell and the magnitude of changes evoked by these stimuli. Reactions of VMN and LHA neurones were the opposite in most instances. Septal stimulations (at more than 10/sec) always produced inhibition of LHA neurone activity. 6. Intravenous injection of glucose inhibited LHA neurones and accelerated firing of VMN cells. This was true during the day period as well as at night when background activities of VMN and LHA neurones were different from that of the day. 7. Stimulation of the septal area with subthreshold pulses at a low rate (1-0.3/sec) suppressed or altered oscillations in firing frequency of LHA neurones. Severance of connection between LHA and structures caudal thereto had no effect on LHA neurone firing rates or rhythms. Sections between the septal area and LHA, however, abolished or greatly altered the oscillatory rhythms of LHA cell activity, although spontaneous discharges continued at a somewhat lower rate for periods of hours. 8. Stimulation of suprachiasmatic nuclei with weak intensity and low frequency also changed oscillatory fluctuations in firing of LHA neurones. 9. Possible origins of circadian rhythm and oscillations of short duration in firing pattern of VMN and LHA neurones were discussed.
The suprachiasmatic nuclei generate a circadian rhythm which can be described by period, phase and amplitude variables. Evidence is accumulating that the three descriptors of circadian rhythmicity can be modulated independently by several brain structures. This report describes the effects of lateral hypothalamic (LHA) damage on control of period, phase and amplitude of the hamster locomotor rhythm. Adult male hamsters received bilateral electrolytic lesions of the far lateral LHA. These lesions had no effect on the circadian period in constant dim, but significantly advanced the onset of nocturnal wheel running and lengthened the duration of the activity phase. Rate of reentrainment after a 6-h phase advance or delay was not affected by the lesion. Rhythm amplitude, as indicated by the number of wheel revolutions per day, was not affected by the lesions. The results support the view that different brain regions can exert independent modulatory control over the basic circadian rhythm generated by the suprachiasmatic nucleus.
Neuropeptide Y (NPY) injected into the paraventricular nucleus (PVN) is known to elicit a powerful feeding response in satiated, brain-cannulated rats. The present experiment investigates the effect of peptide YY (PYY), a structurally-related peptide, on feeding behavior and, in addition, the effects of both PYY and NPY on the pattern of macronutrient selection. Injection of PYY directly into the PVN, in doses ranging from 7.8 to 235 pmol/0.3 microliters, caused a strong, dose-dependent stimulation of feeding behavior, as well as a small stimulation of drinking behavior, in satiated rats. The mean latency to eat was 9.3 min, with substantial feeding occurring within 30 min of the injection. At low doses, the increase in feeding was seen predominantly during the first hr. At the highest dose, in contrast, food intake continued to increase progressively over the next few hr. such that by 4 hr postinjection food intake was more than 20 g over vehicle baseline. In 1 hr tests with 3 pure macronutrient (protein, fat and carbohydrate) diets simultaneously available, PYY and NPY (78 pmol/0.3 microliters) both elicited a strong and selective increase in carbohydrate consumption, with little or no effect on protein or fat consumption. These results suggest that hypothalamic receptors sensitive to PYY and NPY may participate in the control of carbohydrate consumption.
IT is generally accepted that the lateral hypothalamic area (LH) and ventromedial nucleus (VMH) have a reciprocal relationship in the control of feeding behaviour1-3, and that some neurones in these regions are sensitive to levels of glucose in the blood4,5 or to electro-osmotically applied glucose6. We have demonstrated that although about one-third of the VMH neurones increased their activity when glucose was applied, there are neurones in LH which are specifically inhibited by it. These neurones are activated by direct applications of insulin, 2-deoxy-D-glucose and 3-O-methyl-D-glucose7. Booth8 demonstrated that the injection of 1 µl of 5% D-glucose in the LH blocked insulin-induced eating. More recently Colin-Jones and Himsworth9 reported that an injection of 2-deoxy-D-glucose (2DG) into the LH causes a marked increase in gastric acid secretion and attributed it to the lack of metabolisable glucose in the LH neurones. The fact that the specific glucose-sensitive cells which are inhibited by glucose exist only in LH has been highlighted in a recent report in which gastric secretion induced by the peripheral administration of 2DG in the cat was blocked by specific and discrete lesions in the lateral hypothalamus10. Here we report that the inhibition of LH neurones induced by direct application of glucose is the result of membrane hyperpolarisation and possibly results from the activation of the sodium pump causing an increased extrusion of internal sodium.
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.
Observations that a pancreatic polypeptide-like substance, possibly neuropeptide Y, is present in hypothalamic areas and may coexist with catecholamines prompted evaluation of its role in controlling feeding behavior. Intracerebroventricular administration of 2 or 10 micrograms of human pancreatic polypeptide to ovariectomized rats pretreated with estradiol benzoate plus progesterone significantly increased the number of animals feeding, and total food intake in tests conducted during the light phase of the day. Administration of neuropeptide Y, 2 or 10 micrograms, induced feeding in all rats, and food intake was 3 times greater than that observed after human pancreatic polypeptide injection. These findings imply that neuropeptide Y, or a closely related pancreatic polypeptide-like neuropeptide, plays an important role in neural regulation of feeding behavior.
Acute central administration of galanin has been reported to increase fat consumption. These experiments were designed to test the hypothesis that repeated injections of galanin would elicit hyperphagia and weight gain and that this response would depend on the available diet. Male Sprague-Dawley rats were fed high (56% energy) or low (10% energy) fat diets. Galanin (300 pmol) or saline vehicle was injected into the third ventricle twice daily for 7 days and three times daily for another 6 days. On both the high-carbohydrate and high-fat diets, twice daily galanin increased daytime food intake, but there was a compensatory decrease in nighttime intake. The addition of a third, nighttime injection of galanin was ineffective in producing an increase in total 24-h intake. There was no significant increase in body weight during galanin treatment in rats eating either diet although animals eating the high-fat diet gained more weight as reflected by a significant increase in epididymal fat pad weight. Galanin treatment had no effects on serum insulin, glucose or corticosterone concentrations, measured at the end of the experiment. However, animals fed the high-fat diet had significantly higher insulin concentrations at the time of sacrifice. Although repeated central infusions of galanin reliably stimulated daytime intake of both diets, they failed to increase total daily energy intake or body weight.
Intracerebroventricular neuropeptide Y (NPY) administration to normal rats for 7 days produced a sustained, threefold increase in food intake, resulting in a body weight gain of more than 40 g. Basal plasma insulin and triglyceride levels were increased in NPY-treated compared to vehicle-infused rats by about four- and two-fold, respectively. The glucose utilization index of white adipose tissue, measured by the labelled 2-deoxy-D-glucose technique was four times higher in NPY-treated rats compared to controls. This change was accompanied by an increase in the insulin responsive glucose transporter protein (GLUT 4). In marked contrast, muscle glucose utilization was decreased in NPY-treated compared to vehicle-infused animals. This change was accompanied by an increase in triglyceride content. When NPY-treated rats were prevented from overeating, there was no decrease in muscle glucose uptake, nor was there an increase in muscle triglyceride content. This suggests that muscle insulin resistance of ad libitum-fed NPY-treated rats is due to a glucose-fatty acid (Randle) cycle. When intracerebroventricular NPY administration was stopped and rats kept without any treatment for 7 additional days, all the abnormalities brought about by the neuropeptide were normalized. A tonic central effect of NPY is therefore needed to elicit and maintain most of the hormonal and metabolic abnormalities observed in the present study. Such abnormalities are analogous to those seen in the dynamic phase of obesity syndromes in which high hypothalamic NPY levels have been reported.
Chronic intracerebroventricular (icv) administration of neuropeptide-Y (NPY; 10 micrograms/day) was performed in normal female rats to investigate its hormonal and metabolic consequences. Intracerebroventricular NPY produced hyperphagia, increased basal insulinemia, as well as liver and adipose tissue lipogenic activity. It also increased basal morning corticosteronemia. When NPY-induced hyperphagia was prevented by pair-feeding, the icv NPY treatment resulted in the same increases in basal insulinemia and corticosteronemia, and liver and white adipose tissue lipogenesis was still higher than that in respective controls. Under the ad libitum and pair-feeding conditions, icv NPY stimulated glucose uptake as well as total lipoprotein lipase activity in white adipose tissue; it resulted in an increase total activity of hepatic and white adipose tissue acetyl coenzyme-A-carboxylase. As all hormonal and metabolic changes elicited by icv NPY remained present (at the same or to a lesser extent depending upon the parameter considered) when hyperphagia was prevented by pair-feeding, it was, thus, shown that icv NPY per se induces peripheral hormonal and metabolic alterations via efferent routes, which remain to be determined. The effects of icv NPY reported in this study are similar to the defects observed in the early phase of genetic obesity in rodents, the hypothalamus of which has increased NPY levels. NPY could, thus, be of relevance in the occurrence of genetically induced obesity.
This article reviews findings that have accumulated since the original description of the syndrome that follows destruction of the lateral hypothalamic area (LHA). These data comprise the areas of neuroanatomy, body weight regulation, neuroendocrinology, neurochemistry, and intermediary metabolism. Neurons in the LHA are the largest in the hypothalamus, and are topographically well organized. The LHA belongs to the parasympathetic area of the hypothalamus, and connects with all major parts of the brain and the major hypothalamic nuclei. Rats with LHA lesions regulate their body weight set point in a primary manner and not because of destruction of a "feeding center". The lower body weight is not due to finickiness. In the early stages of the syndrome, catabolism and running activity are enhanced, and so is the activity of the sympathetic nervous system (SNS) as shown by increased norepinephrine excretion that normalizes one mo later. The LHA plays a role in the feedback control of body weight regulation different from ventromedial (VMN) and dorsomedial (DMN). Tissue preparations from the LHA promote glucose utilization and insulin release. Although it does not belong to the classical hypothysiotropic area of the hypothalamus, the LHA does affect neuroendocrine secretions. No plasma data on growth hormone are available following electrolytic lesions LHA but electrical stimulation fails to elicit GH secretion. Nevertheless, antiserum raised against the 1-37 fragment of human GHRF stains numerous perikarya in the dorsolateral LHA. The plasma circadian corticosterone rhythm is disrupted in LHA lesioned rats, but this is unlikely due to destruction of intrinsic oscillators. Stimulation studies show a profound role of the LHA in glucose metabolism (glycolysis, glycogenesis, gluconeogenesis), this mechanism being cholinergic. Its role in lipolysis appears not to be critical. In general, stimulation of the VMN elicits opposite effects. Lesion studies in rats show altered in vitro glucose carbon incorporation into several tissue fractions both a few days, and one mo after lesion production. Several of these changes may be due to the reduced food intake, others appear to be due to a "true" lesion effect.
The effect of acute intracerebroventricular (i.c.v.) injection of neuropeptide Y (NPY) on basal and glucose- or arginine-stimulated insulinemia was studied in anesthetized and conscious rats. Basal insulinemia was not significantly increased relative to control values after NPY injection. The insulinemic response to an intravenous bolus of glucose or arginine was unaffected by prior NPY injection, glycemic profiles being identical in control and NPY-injected rats. Plasma NPY concentrations were double the corresponding control values at 20 min after i.c.v. NPY injection, but this difference was not statistically significant. Although peripheral NPY inhibits insulin secretion, these elevated plasma NPY concentrations occurred too late to explain the lack of effect of i.c.v. NPY on substrate-induced insulin secretion. Compared to control rats, marked increases in corticosteronemia were observed after i.c.v. NPY injection in conscious animals. When allowed to eat ad libitum at the end of each experiment, NPY-injected rats consumed significantly more chow in 20 min than controls. We conclude that although acute i.c.v. injection of a maximum dose of NPY had definite effects on plasma corticosterone concentrations and feeding, it favored neither the basal nor the substrate-induced insulin output.
The hypothalamus plays a central role in the integrated control of feeding and energy homeostasis. We have identified two novel neuropeptides, both derived from the same precursor by proteolytic processing, that bind and activate two closely related (previously) orphan G protein-coupled receptors. These peptides, termed orexin-A and -B, have no significant structural similarities to known families of regulatory peptides. prepro-orexin mRNA and immunoreactive orexin-A are localized in neurons within and around the lateral and posterior hypothalamus in the adult rat brain. When administered centrally to rats, these peptides stimulate food consumption. prepro-orexin mRNA level is up-regulated upon fasting, suggesting a physiological role for the peptides as mediators in the central feedback mechanism that regulates feeding behavior.
The assimilation, storage and use of energy from nutrients constitute a homeostatic system that is essential for life. In vertebrates, the ability to store sufficient quantities of energy-dense triglyceride in adipose tissue allows survival during the frequent periods of food deprivation encountered during evolution. However, the presence of excess adipose tissue can be maladaptive. A complex physiological system has evolved to regulate fuel stores and energy balance at an optimum level. Leptin, a hormone secreted by adipose tissue, and its receptor are integral components of this system. Leptin also signals nutritional status to several other physiological systems and modulates their function. Here we review the role of leptin in the control of body weight and its relevance to the pathogenesis of obesity.
Orexin A and orexin B were microinjected into the perifornical hypothalamus (PFH), lateral hypothalamus (LH), hypothalamic paraventricular nucleus (PVN), and ventral tegmental area (VTA) of male Sprague-Dawley rats. Orexin B (15 nmol) was also injected into the lateral cerebral ventricle (i.c.v.). Orexin A (>/=500 pmol) stimulated feeding in the PFH and LH, but not in the VTA or PVN. Orexin B stimulated feeding only when injected i.c.v.
Ž POMC and neuropeptide Y NPY are targets of leptin signaling in the hypothalamus, Endocrinology 139 2 wx 17 A Acute intracerebroventricular administration of neuropeptide Y stim-ulates corticosterone output and feeding but not insulin output in normal rats
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- Ž Nt
- F Sainsbury
- E Rohner-Jeanrenaud
- B Grouzmann
- Jeanrenaud
centrating hormone MCH , neurotensin NT , proopiomelanocortin Ž.Ž POMC and neuropeptide Y NPY are targets of leptin signaling in the hypothalamus, Endocrinology 139 2 wx 17 A. Sainsbury, F. Rohner-Jeanrenaud, E. Grouzmann, B. Jeanrenaud, Acute intracerebroventricular administration of neuropeptide Y stim-ulates corticosterone output and feeding but not insulin output in normal rats, Neuroendocrinology 63 4 wx 18 T. Sakurai, A. Amemiya, M. Ishii, I. Matsuzaki, R.M. Chemelli, H
Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocre- Ž. Ž tinrorexin Jeanre-naud, Induction and reversibility of an obesity syndrome by intrac-erebroventricular neuropeptide Y administration to normal rats
- R Belousov
- N Vettor
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- B Rohner-Jeanrenaud
Belousov, Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocre- Ž. Ž tinrorexin, J. Neurosci. 18 19 wx 23 R. Vettor, N. Zarjevski, I. Cusin, F. Rohner-Jeanrenaud, B. Jeanre-naud, Induction and reversibility of an obesity syndrome by intrac-erebroventricular neuropeptide Y administration to normal rats, Dia- Ž. Ž
Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems
- Broberger
Leptin and the regulation of body weight in mammals
- Friedman
Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight
- Rossi
Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity
- Zarjevski
Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y
- Erickson
Evidence suggesting that galanin (GAL), melanin-concentrating hormone (MCH), neurotensin (NT), proopiomelanocortin (POMC) and neuropeptide Y (NPY) are targets of leptin signaling in the hypothalamus
- Sahu