High-Fat Diet Induces Diabetogenic Alteration of Ventromedial Hypothalamus (VMH) Glucose Sensing Neurons That Is Reversed by Circadian-Timed Bromocriptine Treatment

Abstract

The VMH is a glucose sensing center that elicits the counterregulatory response to local glucopenia. However, VMH sensing of local post-meal hyperglycemia can potentiate post-meal peripheral insulin action. The insulin resistant (IR) state is coupled to postprandial hyperglycemia and may derive from a shift in glucose sensing status in VMH. To test this postulate in vivo electrophysiological multi-unit responses (MURs) to local glucose (1-5 mM) or 2-deoxyglucose (2-DG, 1-15 mM) infusion at VMH were obtained and compared from rats (age 12 weeks, on 14 hour daily photoperiods) maintained for 5 weeks on either regular lab chow (RC, 18% of calories from fat) or high fat diet (HFD, 60% of calories from fat) (to induce the IR state) (N= 8 RD, 10 HFD). The impact of circadian-timed bromocriptine (BC) (10 mg/kg), a dopamine D2 receptor agonist and postprandial insulin sensitizer vs. vehicle (N=5-7/group), upon MURs in HFD rats was also examined. Relative to VMH MURs of RC rats, in HFD rats VMH MURs to local hyperglycemia were reduced 53% (P<.05) and MURs to 2-DG-induced hypoglycemia were elevated 93% (P<.05). Neuronal receiver operator characteristic analyses suggest these changes in MUR rates (VMH output activity) can significantly alter the brain’s ability to detect and respond appropriately to such changes in VMH physiological glucose levels. BC treatment of HFD rats at circadian time (CT) of daily waking, but not outside this CT window reduced VMH MUR to 2-DG and increased VMH MUR to hyperglycemia to levels observed in rats on RC diet (P<.02-DG, p<.001 glucose) accompanied by reduced blood glucose (12%, P<.001) and hyperinsulinemia (66%, P<.05). These findings indicate that the VMH glucose sensing apparatus is altered by HFD to facilitate hyperglycemia and inhibit post-meal insulin action at physiological glucose levels and that this perturbation of the HFD can be abrogated by circadian-timed bromocriptine administration. Disclosure C. Stoelzel: Employee; Self; VeroScience, LLC. E. Duvallet: Employee; Self; VeroScience, LLC. Y. Zhang: Employee; Self; VeroScience, LLC. T. Tsai: Employee; Self; VeroScience, LLC. M. Ezrokhi: Employee; Self; VeroScience, LLC. A. Cincotta: Employee; Self; VeroScience, LLC.. Stock/Shareholder; Self; VeroScience, LLC..