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Title: The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis

Author
item GUAN, XINFU - Children'S Nutrition Research Center (CNRC)

Submitted to: American Journal of Physiology - Regulatory Integrative & Comparative Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/30/2014
Publication Date: 7/2/2014
Citation: Guan, X. 2014. The CNS glucagon-like peptide-2 receptor in the control of energy balance and glucose homeostasis. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 307: R585-R596.

Interpretive Summary: Obesity has become a global epidemic. The prevalence of overweight and obesity keeps rising in the United States: 2/3 of adults and 1/3 of children are overweight or obese. The global obesity epidemic is a result of the complex interplay. However, biological mechanisms underlying obesity and diabetes are not clear. Obesity occurs due to an imbalance of energy intake and energy expenditure, in which energy intake is more than energy expenditure. Energy balance is controlled by the brain in response to nutritional and hormonal signals from the gut. Gut hormones play a key role in the regulation of energy balance and blood glucose. Using genetics and pharmacology, we have elucidated that a gut hormone, named glucagon-like peptide-2 (GLP-2) secreted in response to energy intake, has a significant impact on energy metabolism and insulin responsiveness. GLP-2 is a key mediator for metabolic improvement and body weight loss after bariatric surgery. Moreover, we have demonstrated the physiological role of GLP-2-targeted protein (i.e., GLP-2 receptor) in the brain in suppressing feeding behavior, gastrointestinal motility, and hepatic glucose production. Activation of GLP-2 receptor in the brain stimulates neuronal activities and signaling pathways. We show that the GLP-2 receptor in the brain plays a physiological role in the control of food intake and glucose homeostasis; and propose that GLP-2-mediated neural circuitries and signaling pathways are responsible for energy intake-inhibiting effects. This study will help to identify innovative dietary interventions for the prevention and treatment of children's obesity, metabolic syndrome, and diabetes.

Technical Abstract: The gut-brain axis plays a key role in the control of energy balance and glucose homeostasis. In response to luminal stimulation of macronutrients and microbiotaderived metabolites (secondary bile acids and short chain fatty acids), glucagon-like peptides (GLP-1 and -2) are cosecreted from endocrine L cells in the gut and coreleased from preproglucagonergic neurons in the brain stem. Glucagon-like peptides are proposed as key mediators for bariatric surgery-improved glycemic control and energy balance. Little is known about the GLP-2 receptor (Glp2r)-mediated physiological roles in the control of food intake and glucose homeostasis, yet Glp1r has been studied extensively. This review will highlight the physiological relevance of the central nervous system (CNS) Glp2r in the control of energy balance and glucose homeostasis and focuses on cellular mechanisms underlying the CNS Glp2r-mediated neural circuitry and intracellular PI3K signaling pathway. New evidence (obtained from Glp2r tissue-specific KO mice) indicates that the Glp2r in POMC neurons is essential for suppressing feeding behavior, gastrointestinal motility, and patic glucose production. Mice with Glp2r deletion selectively in POMC neurons exhibit hyperphagic behavior, accelerated gastric emptying, glucose intolerance, and hepatic insulin resistance. GLP-2 differentially modulates postsynaptic membrane excitability of hypothalamic POMC neurons in Glp2r- and PI3Kdependent manners. GLP-2 activates the PI3K-Akt-FoxO1 signaling pathway in POMC neurons by Glp2r-p85 alpha interaction, Intracerebroventricular GLP-2 augments glucose tolerance suppresses glucose production, and enhances insulin sensitivity, which require PI3K (p110 alpha) activation in POMC neurons. Thus, the CNS Glp2r plays a physiological role in the control of food intake and glucose homeostasis. This review will also discuss key questions for future studies.