Central Fructose Impairs Exendin 4‐Mediated Anorexia in the Ventromedial Hypothalamus in Male C57Bl/6 Mice

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Glucagon‐like peptide‐1 (Glp1) is a gut hormone that stimulates insulin secretion but also promotes satiety via actions on the central nervous system. As such, Glp1 receptor (Glp1r) agonists are currently being developed as therapeutics for body weight control. We have previously shown that pharmacological activation of the Glp1r in the ventromedial hypothalamus (VMH) by the Glp1r agonist Exendin‐4 (Ex4) suppresses food intake via stimulation of intracellular glucose metabolism and inhibition of the cellular nutrient sensor AMP‐activated protein kinase (AMPK). This raises the possibility that interference with these nutrient‐sensing mechanisms may attenuate the anorectic effect of Glp1r agonists in the brain. The dietary monosaccharide fructose is an AMPK activator, and intracerebroventricular (ICV) fructose attenuates the anorectic effect of ICV Ex4. The relevance of this finding is underscored by evidence supporting an association between excessive dietary fructose consumption (e.g., high fructose corn syrup, sucrose) and the obesity epidemic. The aim of these studies was to assess whether fructose also impairs Ex4‐mediated anorexia in the VMH. Male C57Bl/6 mice were maintained on a chow diet and were instrumented with bilateral cannulae targeting the VMH for delivery of Ex4 following (1) VMH‐targeted or (2) orally‐gavaged pre‐treatment with fructose, glucose or vehicle. In additional studies, animals were challenged with a high fructose (vs. carbohydrate control) diet for 15wks prior to treatment with Ex4 in the VMH. 18‐h food intake, energy expenditure (EE) and locomotor activity were assessed using a Comprehensive Lab Animal Monitoring System. VMH‐targeted fructose significantly attenuated the food intake‐suppressive effect of VMH Ex4 but had no effect on EE. VMH‐targeted glucose, however, did not potentiate the anorectic effect of Ex4. Orally‐dosed fructose did not impair the anorectic effect of Ex4 in the VMH, nor did dietary fructose. Similarly, orally‐dosed glucose did not potentiate the anorectic effect of Ex4 in the VMH. In conclusion, although fructose impairs the ability of Ex4 to reduce food intake when targeted to the VMH, it is not an inhibitor of VMH Glp1r action on food intake when it is administered along an ingested route (i.e., either orally or dietary). However, these observations validate the role of AMPK as a mediator of the anorectic effect of Ex4 in the VMH. Further elucidation of the interactions between fructose and Glp1r‐mediated signaling in the brain could be beneficial in developing more effective anti‐obesity therapies.Support or Funding InformationThis work was supported by NIH R01 1R01DK097361 to Julio AyalaThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.