Central Glucagon-Like Peptide 1 Receptor (Glp1r)-Induced Anorexia Requires Glucose Metabolism-Mediated Suppression of AMPK and is Impaired by Central Fructose.
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.
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ABSTRACT: Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and endocrine pathways. Here we contrast the pharmacology and physiology of incretin hormones and review recent advances in mechanisms coupling incretin receptor signaling to pleiotropic metabolic actions in preclinical studies. We discuss whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies.Cell metabolism 05/2013; DOI:10.1016/j.cmet.2013.04.008 · 16.75 Impact Factor
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ABSTRACT: The fruit fly, Drosophila melanogaster is a broadly used model for gerontological research. Many studies are dedicated to understanding nutritional effects on ageing; however, the influence of dietary carbohydrate type and dosage is still poorly understood. We show that among three carbohydrates tested, fructose, glucose, and sucrose, the latter decreased life span by 13%-27%, being present in concentrations of 2%-20% in the diet. Life-span shortening by sucrose was accompanied by an increase in age-independent mortality. Sucrose also dramatically decreased the fecundity of the flies. The differences in life span and fecundity were determined to be unrelated to differential carbohydrate ingestion. The highest mitochondrial protein density was observed in flies fed sucrose-containing diet. However, this parameter was not affected by carbohydrate amount in the diet. Fly sensitivity to oxidative stress, induced by menadione, was increased in aged flies and was slightly affected by type and concentration of carbohydrate. In general, it has been demonstrated that sucrose, commonly used in recipes of Drosophila laboratory food, may shorten life span and lower egg-laying capability on the diets with very low protein content.The Journals of Gerontology Series A Biological Sciences and Medical Sciences 05/2013; DOI:10.1093/gerona/glt077 · 4.98 Impact Factor
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ABSTRACT: Glucagon-like peptide-1 (GLP-1) receptors (GLP-1R) expressed in the nucleus tractus solitarius (NTS) are physiologically required for the control of feeding. Recently, NTS GLP-1R-mediated suppression of feeding was shown to occur via a rapid PKA-induced suppression of AMPK and activation of MAPK signaling. Unknown are the additional intracellular signaling pathways that account for the long-term hypophagic effects of GLP-1R activation. As cAMP/PKA activity can promote PI3K-PIP3-dependent translocation of Akt to the plasma membrane, we hypothesize that hindbrain GLP-1R-mediated control of feeding involves a PI3K-Akt-dependent pathway. Importantly, the novel evidence presented here challenges the dogmatic view that PI3K phosphorylation results in an obligatory activation of Akt, and instead supports a growing body of literature showing that activation of cAMP/PKA can inhibit Akt phosphorylation at the plasma membrane. Behavioral data show that inhibition of hindbrain PI3K activity by 4(th) icv administration of LY-294002 (3.07µg) attenuated the food intake- and body weight-suppressive effects of 4th icv administration of the GLP-1R agonist exendin-4 (0.3µg) in rats. Hindbrain administration of triciribine (10µg), an inhibitor of PIP3-dependent translocation of Akt to the cell membrane, also attenuated the intake-suppressive effects of 4(th) icv exendin-4. Immunoblot analyses of ex-vivo NTS tissue lysates and in-vitro GLP-1R-expressing neurons (GT1-7) support the behavioral findings and show that GLP-1R activation decreases phosphorylation of Akt in a time-dependent fashion. Current data reveal the requirement of PI3K activation, PIP3-dependent translocation of Akt to the plasma membrane, and suppression in phosphorylation of membrane-bound Akt to mediate the food intake-suppressive effects of hindbrain GLP-1R activation.AJP Endocrinology and Metabolism 07/2013; DOI:10.1152/ajpendo.00367.2013 · 4.09 Impact Factor