Food and Behaviour Research

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Central Glucagon-Like Peptide 1 Receptor (Glp1r)-Induced Anorexia Requires Glucose Metabolism-Mediated Suppression of AMPK and is Impaired by Central Fructose

Burmeister MA, Ayala JE, Drucker DJ, Ayala JE. (2013) Am J Physiol Endocrinol Metab.   Jan 22. [Epub ahead of print] 

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Abstract:

Glucagon-like peptide-1 (Glp1) suppresses food intake via activation of a central (i.e., brain) Glp1 receptor (Glp1r). 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 Glp1r activation is attenuated by the AMPK stimulator AICAR. This suggests that central Glp1r activation suppresses food intake via inhibition of central AMPK.

The present studies examined the mechanism(s) by which central Glp1r activation inhibits AMPK. Supporting previous findings, AICAR attenuated the anorectic effect elicited by intracerebroventricular (ICV) administration of the Glp1r agonist Exendin-4 (Ex4).

We demonstrate that Ex4 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 Ex4 requires central glucose metabolism.

Supporting this, the glycolytic inhibitor 2-deoxyglucose (2-DG) attenuated the anorectic effect of Ex4. However, ICV glucose did not enhance the suppression of food intake by Ex4. AICAR had no effect on Ex4-mediated reduction in locomotor activity.

We also tested whether other carbohydrates affect the anorectic response to Ex4. ICV pre-treatment with the sucrose metabolite fructose, an AMPK activator, attenuated the anorectic effect of Ex4. This potentially explains the increased food intake observed in sucrose-fed mice.

In summary, we propose a model whereby activation of the central Glp1r reduces food intake via glucose metabolism-dependent inhibition of central AMPK. We also suggest that fructose stimulates food intake by impairing central Glp1r action.

This has significant implications given the correlation between sugar consumption and obesity.