Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system

Fan, Wei; Ellacott, Kate L. J.; Halatchev, Ilia G.; Takahashi, Kanji; Yu, Pinxuan; Cone, Roger D.

doi:10.1038/nn1214

Cited by 265 publications

(203 citation statements)

References 14 publications

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“…Additionally, MC4R rs17782313(C) polymorphism may alter the expression of MC4R receptors located on efferent vagal neurons; these MC4R receptors on vagal neurons are known to be associated with increased satiation and regulation of gastric function (Balthasar et al 2005;Fan et al 2004;Gautron et al 2010;Wan et al 2008). Further studies are needed to determine whether MC4R agonist targeting obesity and metabolic syndrome would have different effects depending on the genotype of the rs17782313 polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

et al. 2014

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Melanocortin 4 receptor (MC4R) has a major role in energy homeostasis. The rs17782313 polymorphism, mapped 188 kb downstream from MC4R, has been associated with satiety, higher body mass index (BMI) and total calorie intake in adults. To assess the association of rs17782313 with gastric functions, satiation, or satiety, we studied 178 predominantly Caucasian overweight and obese people: 120 females, 58 males; mean BMI 33.4 ± 5.3 kg/m 2 (SD); age 37.7 ± 11.2 years. Quantitative traits assessed were gastric emptying (GE) of solids and liquids; fasting and postprandial gastric volume; satiation by maximum tolerated volume and 4 symptoms by 100-mm visual analog scales (VAS); and satiety by ad libitum buffet meal. Associations of genotype and quantitative traits were assessed by analysis of covariance (using gender and BMI as covariates), based on a dominant [TC (n = 72) -CC (n = 12) vs. TT (n = 94)] genetic model. rs17782313(C) was associated with postprandial satiation symptoms (median D total VAS 26.5 mm, p = 0.036), reduced proportion of solid GE at 2 h (median D 6.7 %, p = 0.008) and 4 h (median D 3.2 %, p = 0.006), and longer t (median D 6 min, p = 0.034). Associations of rs17782313 with obesity may be explained by reduced satiation and GE. The role of MC4R mechanisms in satiation and gastric function deserves further study.

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Section: Discussionmentioning

confidence: 99%

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

et al. 2014

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“…This is surprising because 2CR are expressed in both the Arc and PVN (27,28), because pharmacological data implicate both the PVN and Arc in the serotonergic control of eating (50,59), because 2CR-serotonergic inputs to the Arc-PVN melanocortinergic neurons appear to be part of the physiological control of eating in mice (3,36,38), and because both the PVN and the Arc have been implicated in the satiating action of CCK (13,17,35,37,38,42). Furthermore, the absence of CCK-induced c-Fos activation in the NTS of 2CR KO mice suggests that NTS-tohypothalamus signaling would be reduced.…”

Section: Discussionmentioning

confidence: 99%

Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors

Asarian

2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Asarian L. Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors. Am J Physiol Regul Integr Comp Physiol 296: R51-R56, 2009. First published November 12, 2008 doi:10.1152/ajpregu.90655.2008.-To investigate the role of serotonin 2C receptors (2CR), which are expressed only in the central nervous system, in the satiating actions of the gut peptides CCK and glucagon-like peptide 1 (GLP-1), we examined 1) the effect of null mutations of serotonin 2CR (2CR KO) on the eating-inhibitory potencies of dark-onset intraperitoneal injections of 0.9, 1.7, or 3.5 nmol/kg (1, 2, or 4 g/kg) CCK and 100, 200, and 400 nmol/kg (33, 66, or 132 g/kg) GLP-1, and 2) the effects of intraperitoneal injections of 1.7 nmol//kg CCK and 100 nmol/kg GLP-1 on neuronal activation in the brain, as measured by c-Fos expression. All CCK and GLP-1 doses decreased 30-min food intake in wild-type (WT) mice, but none of them did in 2CR KO mice. CCK increased the number of cells expressing c-Fos in the nucleus tractus solitarii (NTS) of WT, but not 2CR KO mice. CCK induced similar degrees of c-Fos expression in the paraventricular (PVN) and arcuate (Arc) nuclei of the hypothalamus of both genotypes. GLP-1, on the other hand, increased c-Fos expression similarly in the NTS of both genotypes and increased c-Fos expression more in the PVN and Arc of 2CR KO mice, but not WT mice. These results indicate that serotonin signaling via serotonin 2CR is necessary for the full satiating effects of CCK and GLP-1. In addition, they suggest that the satiating effects of the two peptides are mediated by different neural mechanisms. endocrine; eating; hormone; neural; immunocytochemistry; 5HT ON THE BASIS OF FULFILLMENT of criteria for endocrine satiation signals initially proposed by Gibbs et al. (20), intestinal CCK and GLP-1 are now considered to be physiological controls of eating (4,10,19,32). Both hormones are released during meals, and premeal administration of doses producing plasma hormone levels that are similar to prandial levels is sufficient to inhibit meal size in the absence of adverse effects in humans. Furthermore, administration of CCK 1 receptor antagonists in humans or rats, or GLP-1 receptor antagonists in rats, increases food intake (Williams D, personal communication); CCK 1 receptor antagonists also block the satiating effects of CCK secretagogues in humans and rats. Although the understanding of the roles of these peptides in physiology of eating has increased tremendously in the last two decades (19,39,41,54), the brain mechanisms underlying their effects are still unclear.Serotonin appears to be a key neurotransmitter in the central mediation of eating, including the control of meal size. Extracellular concentrations of serotonin and its metabolite 5-HIAA increase in rats' brains during spontaneous meals (44). The serotonin agonist fenfluramine, which both releases synaptic serotonin and blocks serotonin reuptake (14, 21), inhibits eating in rats by reducing meal size without affectin...

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“…This brainstem-based satiation process likely involves the activation of neurochemically specific NTS neurons such as the A2 catecholaminergic neurons (Rinaman et al, 1995;Rinaman, 2003), GLP-1 expressing neurons (Vrang et al, 2003)(ref), and POMCexpressing neurons in the commissural NTS (Fan et al, 2004).…”

Section: Vagal and Other Autonomic Hindbrain Mechanisms Involved In Fmentioning

confidence: 99%

The vagus nerve, food intake and obesity

Berthoud

2008

Regulatory Peptides

258

195

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Food interacts with sensors all along the alimentary canal to provide the brain with information regarding its composition, energy content, and beneficial effect. Vagal afferents innervating the gastrointestinal tract, pancreas, and liver provide a rapid and discrete account of digestible food in the alimentary canal, as well as circulating and stored fuels, while vagal efferents together with the sympathetic nervous system and hormonal mechanisms codetermine the rate of nutrient absorption, partitioning, storage, and mobilization. Although vagal sensory mechanisms play a crucial role in the neural mechanism of satiation, there is little evidence suggesting a significant role in long-term energy homeostasis. However, increasing recognition of vagal involvement in the putative mechanisms making bariatric surgeries the most effective treatment for obesity should greatly stimulate future research to uncover the many details regarding the specific transduction mechanisms in the periphery and the inter-and intra-neuronal signaling cascades disseminating vagal information across the neuraxis.

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Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system

Cited by 265 publications

References 14 publications

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

Association of melanocortin 4 receptor gene variation with satiation and gastric emptying in overweight and obese adults

Loss of cholecystokinin and glucagon-like peptide-1-induced satiation in mice lacking serotonin 2C receptors

The vagus nerve, food intake and obesity

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