期刊
DIABETES
卷 66, 期 2, 页码 372-384出版社
AMER DIABETES ASSOC
DOI: 10.2337/db16-1102
关键词
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资金
- Canada Research Chairs program
- Canadian Institutes of Health Research [123391]
- National Institutes of Health [7R01DK082480, 1R01DK107652, 4R01DK097361]
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(Delta Nkx21cre)). We also generated mice lacking Glp1r expression specifically in two GLP-1RA-responsive hypothalamic feeding nuclei/cell types, the paraventricular nucleus (GLP-1RKD(Delta Sim1cre)) and proopiomelanocortin neurons (GLP-1RKD(Delta POMCcre)). Chow-fed GLP-1RKD(Delta Nkx21cre) 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(Delta Sim1cre) and GLP-1RKD(Delta POMCcre) 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(Delta Nkx21cre) 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.
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