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

Citation
Burmeister, Melissa A, et al. “The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient But Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice”. 2017. Diabetes, vol. 66, no. 2, 2017, pp. 372–384.
Center University of Michigan
Author Melissa A Burmeister, Jennifer E Ayala, Hannah Smouse, Adriana Landivar-Rocha, Jacob D Brown, Daniel J Drucker, Doris A Stoffers, Darleen A Sandoval, Randy J Seeley, Julio E Ayala
Abstract

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.

Year of Publication
2017
Journal
Diabetes
Volume
66
Issue
2
Number of Pages
372-384
Date Published
12/2017
ISSN Number
1939-327X
DOI
10.2337/db16-1102
Alternate Journal
Diabetes
PMID
27908915
PMCID
PMC5248999
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