The glucagon-like peptide-1 receptor in the ventromedial hypothalamus reduces short-term food intake in male mice by regulating nutrient sensor activity.

Burmeister MA, Brown JD, Ayala JE, Stoffers DA, Sandoval DA, Seeley RJ, Ayala JE
Am J Physiol Endocrinol Metab. 2017 313 (6): E651-E662

PMID: 28811293 · PMCID: PMC6109646 · DOI:10.1152/ajpendo.00113.2017

Pharmacological activation of the glucagon-like peptide-1 receptor (GLP-1R) in the ventromedial hypothalamus (VMH) reduces food intake. Here, we assessed whether suppression of food intake by GLP-1R agonists (GLP-1RA) in this region is dependent on AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR). We found that pharmacological inhibition of glycolysis, and thus activation of AMPK, in the VMH attenuates the anorectic effect of the GLP-1R agonist exendin-4 (Ex4), indicating that glucose metabolism and inhibition of AMPK are both required for this effect. Furthermore, we found that Ex4-mediated anorexia in the VMH involved mTOR but not acetyl-CoA carboxylase, two downstream targets of AMPK. We support this by showing that Ex4 activates mTOR signaling in the VMH and Chinese hamster ovary (CHO)-K1 cells. In contrast to the clear acute pharmacological impact of the these receptors on food intake, knockdown of the VMH conferred no changes in energy balance in either chow- or high-fat-diet-fed mice, and the acute anorectic and glucose tolerance effects of peripherally dosed GLP-1RA were preserved. These results show that the VMH GLP-1R regulates food intake by engaging key nutrient sensors but is dispensable for the effects of GLP-1RA on nutrient homeostasis.

Copyright © 2017 the American Physiological Society.

MeSH Terms (21)

Acetyl-CoA Carboxylase Adenylate Kinase Animals Body Composition CHO Cells Cricetulus Dose-Response Relationship, Drug Eating Exenatide Food Glucagon-Like Peptide-1 Receptor Glycolysis Homeostasis Male Mice Mice, Inbred C57BL Peptides Sensation TOR Serine-Threonine Kinases Venoms Ventromedial Hypothalamic Nucleus

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