|Guan, Xinfu - Children'S Nutrition Research Center (CNRC)|
|Shi, Xuemei - Children'S Nutrition Research Center (CNRC)|
|Li, Xiaojie - Children'S Nutrition Research Center (CNRC)|
|Chang, Benny - Baylor College Of Medicine|
|Wang, Yi - Children'S Nutrition Research Center (CNRC)|
|Li, Depei - Md Anderson Cancer Center|
|Chan, Lawrence - Baylor College Of Medicine|
Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/18/2012
Publication Date: 7/24/2012
Citation: Guan, X., Shi, X., Li, X., Chang, B., Wang, Y., Li, D., Chan, L. 2012. GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility. American Journal of Physiology - Endocrinology and Metabolism. 303(7):E853-E864.
Interpretive Summary: Among the greatest threats to public health are increasing rates of obesity and diabetes. Gut-derived glucagon-like peptides (GLP-1/2) are proposed as key promoters of metabolic improvements after gastric bypass surgery (the most effective therapy for morbid obesity and diabetes). GLP-2 action in the gut promotes intestinal homeostasis and macronutrient absorption, yet little is known about the physiological relevance of GLP-2 action in the hypothalamus (one region of the brain) in the control of energy balance (such as food intake & gastric emptying). In this study, we genetically generated mutant mice with GLP-2 receptor (Glp2r) deletion in POMC neurons (a population of neurons in the hypothalamus). The POMC-specific Glp2r knockout mice display late-onset obesity as a result of hyperphagic behavior and quick gastric emptying. GLP-2 in the brainstem suppresses food intake and gastric emptying. Thus, our study has demonstrated that Glp2r deficiency in POMC neurons enhances feeding behavior and gastric motility. In contrast, Glp2r activation in the brain suppresses food intake and gastric emptying. This study indicates that GLP-2 in the brain plays a physiological role in the control of feeding behavior and gastric emptying through the central melanocortin system. This study has shed light on how GLP-2 (as a satiety hormone) controls food intake. The translational value of this study would be that GLP-2 may be used to restore feeding behavior and gastric function in obesity and diabetes.
Technical Abstract: 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 cell-specific 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.