1824-P: Leptin Receptor Neurons in the Hypothalamic Ventromedial Nucleus Play a Physiological Role in Regulating Glucose Tolerance

Abstract

A role for leptin receptor (LepR)-expressing neurons in the hypothalamic ventromedial nucleus (VMN) in glucose homeostasis is suggested by studies in which leptin is administered into, or leptin receptors are deleted from, this brain area. However, whether LepR neurons in the VMN play a physiological role in glycemic control remains unknown. To test this hypothesis, we utilized an optogenetics approach to acutely silence VMNLepR neurons in awake, freely moving mice. We found that while photoinhibition of VMNLepR neurons had no effect on blood glucose levels under basal conditions (Control AUC: 681.6 ± 422.4 vs. Inhib AUC: 565.8 ± 350.7; p=ns, n=10), it impaired glucose tolerance significantly (Control AUC: 9251.7 ± 2032.6 vs. Inhib AUC: 13957.4 ± 4837; p<0.01, n=10). Further, this effect occurred despite no change in glucose-stimulated insulin secretion (GSIS), suggesting that the effect is not secondary to reduced insulin secretion. Consistent with this conclusion, we report that insulin sensitivity was reduced by inhibition of VMNLepR neurons based on insulin tolerance testing (Control AUC: 8341 ± 531 vs. Inhib AUC: 9138 ± 658; p<0.01, n=9). Together, these data suggest that VMNLepR neurons play a physiological role in the control of glucose tolerance and that activity of these neurons is required for normal insulin sensitivity. Future studies will examine both the peripheral mechanism(s) that mediate these effects and to identify the underlying neurocircuitry. Disclosure C.L. Faber: None. T.J. Harvey: None. K.R. Velasco: None. V. Damian: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None. Funding National Institutes of Health