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- Title
The Hypothalamic Glucagon-Like Peptide 1 Receptor Is Sufficient but Not Necessary for the Regulation of Energy Balance and Glucose Homeostasis in Mice.
- Authors
Burmeister, Melissa A; Ayala, Jennifer E; Smouse, Hannah; Landivar-Rocha, Adriana; Brown, Jacob D; Drucker, Daniel J; Stoffers, Doris A; Sandoval, Darleen A; Seeley, Randy J; Ayala, Julio E
- 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-1RKDΔNkx2.1cre). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKDΔSim1cre) and proopiomelanocortin neurons (GLP-1RKDΔPOMCcre). Chow-fed GLP-1RKDΔNkx2.1cre 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-1RKDΔSim1cre and GLP-1RKDΔPOMCcre 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-1RKDΔNkx2.1cre 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.
- Subjects
GLUCOSE metabolism; ANIMAL experimentation; ANIMALS; BODY composition; DIET; ENERGY metabolism; GENETIC techniques; GLUCOSE tolerance tests; HOMEOSTASIS; HYPOTHALAMUS; INGESTION; INCRETINS; MICE; NEURONS; PEPTIDES; PROTEIN precursors; RESEARCH funding; VENOM; WEIGHT gain; GLUCAGON-like peptide 1
- Publication
Diabetes, 2016, Vol 65, Issue 12, pN.PAG
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db16-1102