The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.

Burmeister MA, Ayala JE, Smouse H, Landivar-Rocha A, Brown JD, Drucker DJ, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE
Diabetes. 2017 66 (2): 372-384

PMID: 27908915 · PMCID: PMC5248999 · DOI:10.2337/db16-1102

Pharmacological activation of the hypothalamic glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) promotes weight loss and improves glucose tolerance. This demonstrates that the hypothalamic GLP-1R is sufficient but does not show whether it is necessary for the effects of exogenous GLP-1R agonists (GLP-1RA) or endogenous GLP-1 on these parameters. To address this, we crossed mice harboring floxed Glp1r alleles to mice expressing Nkx2.1-Cre to knock down Glp1r expression throughout the hypothalamus (GLP-1RKD). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD) and proopiomelanocortin neurons (GLP-1RKD). Chow-fed GLP-1RKD mice exhibited increased food intake and energy expenditure with no net effect on body weight. When fed a high-fat diet, these mice exhibited normal food intake but elevated energy expenditure, yielding reduced weight gain. None of these phenotypes were observed in GLP-1RKD and GLP-1RKD mice. The acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA exendin-4 and liraglutide were preserved in all mouse lines. Chronic liraglutide treatment reduced body weight in chow-fed GLP-1RKD mice, but this effect was attenuated with high-fat diet feeding. In sum, classic homeostatic control regions are sufficient but not individually necessary for the effects of GLP-1RA on nutrient homeostasis.

© 2017 by the American Diabetes Association.

MeSH Terms (23)

Animals Body Composition Diet, High-Fat Eating Energy Metabolism Exenatide Gene Knockdown Techniques Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide 1 Glucose Glucose Tolerance Test Homeostasis Hypothalamus Incretins Liraglutide Male Mice Neurons Paraventricular Hypothalamic Nucleus Peptides Pro-Opiomelanocortin Venoms Weight Gain

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