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

Aug 17, 2017American journal of physiology. Endocrinology and metabolism

A hormone receptor in the brain’s energy control area reduces short-term eating in male mice by adjusting nutrient sensing

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Abstract

Pharmacological inhibition of glycolysis in the ventromedial hypothalamus reduces the anorectic effect of the GLP-1 receptor agonist exendin-4.

Activation of the GLP-1 receptor in the ventromedial hypothalamus reduces food intake.
Inhibition of glycolysis leads to the activation of AMP-activated protein kinase (AMPK), which diminishes the appetite-suppressing effect of exendin-4.
Regulation of food intake by GLP-1 receptor activation is associated with mammalian target of rapamycin (mTOR) signaling.
Exendin-4 activates mTOR signaling in both the ventromedial hypothalamus and CHO-K1 cells.
Knockdown of the ventromedial hypothalamus does not affect overall energy balance in mice on different diets.

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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 VMHconferred 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. Glp1r

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

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