GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility

Abstract

receptor in POMC neurons suppresses feeding behavior and gastric motility. Am J Physiol Endocrinol Metab 303: E853-E864, 2012. First published July 24, 2012; doi:10.1152/ajpendo.00245.2012.-Glucagon-like peptides (GLP-1/2) are cosecreted from endocrine L cells in the gut and preproglucagonergic neurons in the brain. Peripheral GLP-2 action is essential for maintaining intestinal homeostasis, improving absorption efficiency and blood flow, promoting immune defense, and producing efficacy in treatment of gastrointestinal diseases. However, it is unknown if CNS GLP-2 plays a physiological role in the control of energy homeostasis. Since GLP-1/2 are cotranslated from preproglucagongene and coproduced by prohormone convertase-1, it is challenging to knockout GLP-2 only. Instead, our laboratory has generated a Glp2r-floxed mouse line to dissect cellspecific GLP-2 receptor GLP-2R) action in the regulation of energy balance. Our objective was to determine if GLP-2R in the hypothalamus modulates feeding behavior and gastric emptying. We show that Glp2r mRNA and protein are highly expressed in the arcuate nucleus and dorsomedial nucleus of the mouse hypothalamus. Using the Cre-LoxP system, we generated mice that lack Glp2r expression in POMC neurons (KO; mainly in the hypothalamus). The KO mice showed hyperphagic behavior (such as increases in food intake and meal frequency), accelerated gastric emptying (assessed by [ 13 C]octanoic acid breath test), and late-onset obesity, yet there was no decrease in basal metabolic rate. Infusion of GLP-2 (2.5 nmol into the 4th ventricle) suppressed food intake and gastric emptying, while GLP-2-mediated effects were abolished in the melanocortin receptor-4 (MC4R) KO mice. We conclude that Glp2r deletion in POMC neurons enhances feeding behavior and gastric motility, whereas icv GLP-2R activation suppresses food intake and gastric emptying through the MC4R signaling pathway. This study indicates that CNS GLP-2R plays a physiological role in the control of feeding behavior and gastric emptying and that this is mediated probably through the melanocortin system. glucagon-like peptides; proopiomelanocortin; energy homeostasis; food intake; gastric emptying OBESITY AND TYPE 2 DIABETES affect millions of people and are major health problems in the United States. The hypothalamus, a primary site of convergence and integration in the brain for hormonal and nutritional signals, plays pivotal roles in the regulation of energy balance (42). In the arcuate nucleus (ARC) of the hypothalamus, neurons expressing proopiomelanocortin (POMC neurons) are perfectly positioned to integrate long-term adiposity and short-term satiety signals for energy homeostasis (12). POMC neuronal activation enhances energy expenditure and suppresses food intake, yet neuroendocrine mechanisms are not fully established. Notably, the gastrointestinal (GI) tract has a crucial role in digestion, absorption, and assimilation of nutrients (15), thus controlling energy intake at the first pass. Through the gut-brain axis, gut ho...

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity

“…In addition, knockout mice with GLP2R deletion selectively in hypothalamic arcuate nucleus neurons expressing proopiomelanocortin (POMC) display hyperphagic behaviour and late-onset obesity (Guan et al 2012). These observations support the hypothesis of a physiological role in the regulation of food intake and body weight (Guan et al 2012). Up to date, studies in humans have not demonstrated a decrease in food intake after peripheral GLP2 administration (Schmidt et al 2000, Sørensen et al 2003, even if recent data have shown that intraperitoneal injections of GLP2 or [Gly 2 ]-GLP2 reduce food intake in mice, suggesting a role for GLP2 in the short-term regulation of the eating behaviour (Baldassano et al 2012).…”

“…In fact, intracerebroventricular administrations of GLP2 reduce food intake in rodents (Tang-Christensen et al 2000, Lovshin et al 2001. In addition, knockout mice with GLP2R deletion selectively in hypothalamic arcuate nucleus neurons expressing proopiomelanocortin (POMC) display hyperphagic behaviour and late-onset obesity (Guan et al 2012). These observations support the hypothesis of a physiological role in the regulation of food intake and body weight (Guan et al 2012).…”

“…GLP2R is also expressed in the central nervous system (CNS), specifically in key regions of the brain for energy balance, including the hypothalamus, hippocampus and brainstem (Tang-Christensen et al 2000, Lovshin et al 2004, Guan et al 2012. As a neurotransmitter, GLP2 may mediate preproglucagonergic (PPG) neuron-induced synaptic transmission linking the hypothalamus and the brainstem and may act as a satiation signal in the control of feeding behaviour (Tang-Christensen et al 2000).…”

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

“…MC4R has been associated with key components of nutrient absorption, lipid metabolism, energy expenditure, thermogenesis, adiposity, insulin secretion, food intake, and appetite (Adan et al 2006). Moreover, the MC pathway interacts with other key hormones or pathways such as leptin, 5-HT (Zhou et al 2007), NPY, AGRP, POMC (Biebermann et al 2012), and ANS (Rossi et al 2011;Sohn et al 2013) in the hypothalamus and brainstem (Loos 2011), GLP-1 pathway (Gautron et al 2010), CCK, and vagal afferent fibers (Guan et al 2012).…”

Does gastric bypass surgery change body weight set point?

“…Future experiments should thus use loss-offunction strategies that are either inducible and/or involve more than one signaling pathway. For example, because GLP-2 has been demonstrated to act in addition to GLP-1 on appetite in the brain 56 and the two hormones may substitute for each other, a double GLP-1R/GLP-2R knockout strategy may be necessary. This line of reasoning is supported by studies using octreotide, a nonspecific inhibitor of all gut hormones.…”