Document Detail


GLP-2 receptor in POMC neurons suppresses feeding behavior and gastric motility.
MedLine Citation:
PMID:  22829581     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Xinfu Guan; Xuemei Shi; Xiaojie Li; Benny Chang; Yi Wang; Depei Li; Lawrence Chan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-07-24
Journal Detail:
Title:  American journal of physiology. Endocrinology and metabolism     Volume:  303     ISSN:  1522-1555     ISO Abbreviation:  Am. J. Physiol. Endocrinol. Metab.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-02     Completed Date:  2013-01-07     Revised Date:  2013-10-10    
Medline Journal Info:
Nlm Unique ID:  100901226     Medline TA:  Am J Physiol Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E853-64     Citation Subset:  IM    
Affiliation:
Department of Pediatrics, US Department of Agriculture/Agricultural Research Service Children’s Nutrition Research Center, TX 77030, USA. xguan@bcm.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Arcuate Nucleus / physiology
Dorsomedial Hypothalamic Nucleus / physiology
Feeding Behavior / physiology*
Female
Gastrointestinal Motility / genetics,  physiology*
Glucagon-Like Peptide 2 / pharmacology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neurons / physiology*
Pro-Opiomelanocortin / physiology
Receptor, Melanocortin, Type 4 / genetics,  physiology
Receptors, Glucagon / biosynthesis,  genetics,  physiology*
Signal Transduction / physiology
Grant Support
ID/Acronym/Agency:
DK-075489/DK/NIDDK NIH HHS; DK-084125/DK/NIDDK NIH HHS; K01 DK075489/DK/NIDDK NIH HHS; P30 DK-079638/DK/NIDDK NIH HHS; R01 HL051586/HL/NHLBI NIH HHS; R03 DK084125/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/GLP-2 receptor; 0/Glucagon-Like Peptide 2; 0/MC4R protein, mouse; 0/Receptor, Melanocortin, Type 4; 0/Receptors, Glucagon; 66796-54-1/Pro-Opiomelanocortin
Comments/Corrections

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