Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose

Abstract

Burmeister MA, Ayala J, Drucker DJ, Ayala JE. Central glucagon-like peptide 1 receptor-induced anorexia requires glucose metabolism-mediated suppression of AMPK and is impaired by central fructose. Am J Physiol Endocrinol Metab 304: E677-E685, 2013. First published January 22, 2013 doi:10.1152/ajpendo.00446.2012.-Glucagon-like peptide-1 (GLP-1) suppresses food intake via activation of a central (i.e., brain) GLP-1 receptor (GLP-1R). Central AMP-activated protein kinase (AMPK) is a nutrient-sensitive regulator of food intake that is inhibited by anorectic signals. The anorectic effect elicited by hindbrain GLP-1R activation is attenuated by the AMPK stimulator AICAR. This suggests that central GLP-1R activation suppresses food intake via inhibition of central AMPK. The present studies examined the mechanism(s) by which central GLP-1R activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (icv) administration of the GLP-1R agonist exendin-4 (Ex-4). We demonstrate that Ex-4 stimulates glycolysis and suppresses AMPK phosphorylation in a glucose-dependent manner in hypothalamic GT1-7 cells. This suggests that inhibition of AMPK and food intake by Ex-4 requires central glucose metabolism. Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex-4. However, icv glucose did not enhance the suppression of food intake by Ex-4. AICAR had no effect on Ex-4-mediated reduction in locomotor activity. We also tested whether other carbohydrates affect the anorectic response to Ex-4. Intracerebroventricular pretreatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex-4. This potentially explains the increased food intake observed in sucrose-fed mice. In summary, we propose a model whereby activation of the central GLP-1R reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central GLP-1R action. This has significant implications given the correlation between sugar consumption and obesity.glucagon-like peptide 1; adenosine 5=-monophosphate-activated kinase; food intake; glucose; fructose HEALTH RISKS ASSOCIATED WITH OBESITY, including cardiovascular disease, diabetes, and cancer, highlight the importance of understanding mechanisms that control food intake and how they become impaired. Food intake is regulated by neural and hormonal signals that match caloric intake with the chronic and acute energy needs of the organism. Although significant attention has been given to understanding mechanisms associated with adiposity signals such as leptin and insulin, less is known about acute satiety mechanisms regulated by signals such as glucagon-like peptide-1 (GLP-1).GLP-1 is secreted from intestinal L cells in response to nutrient intake and was identified for its ability to stimulate insulin secretion via activation of a pancreatic ␤-cell GLP-1 receptor (GLP-1R) (3). GLP-1 also r...

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