Identification of Warm-Sensitive Neurons in the Hypothalamic Preoptic Area as Powerful Regulators of Glucose Homeostasis

Abstract

Inhibition of warm sensitive neurons (WSN) in the hypothalamic preoptic area (POA) has been suggested to play a key role in the thermogenic response to cold exposure. As this response is enabled by a marked increase of insulin sensitivity in thermogenic tissues, we hypothesized that WSN inhibition mediates the metabolic as well as the thermogenic response, and therefore that WSN activation would have the opposite effects. To test this hypothesis, we utilized pharmacogenetic technology to activate or inhibit a recently identified subpopulation of POA WSN defined by their expression of the neuropeptide, Pacap, using the drug clozapine-N-oxide (CNO). We report that, as predicted, pharmacogenetic activation of this POA WSN population reduces energy expenditure (EE) (Sal vs. CNO: 0.32±0.10 vs. 0.21±0.02 kcal/hour; p<0.05) and core temperature (Tc) (Sal vs. CNO: 35.4±0.1 vs. 30.4±0.1°C; p=0.0001), while inhibition had the opposite effect (EE: Sal vs. CNO: 0.25±0.03 vs. 0.26±0.03 kcal/hour; Tc: Sal vs. CNO: 35.8±0.1 vs. 36.4±0.2°C; p<0.05). The response to pharmacogenetic activation of POA Pacap+ neurons was quite long-lived (∼2-3 days) and was accompanied by severe glucose intolerance both 1 hour and 24 hour following CNO relative to vehicle treatment (glucose AUC: 3610±1216 for saline vs. 23985±2742 for 1 hour CNO vs. 28459±2411 vs. 24 hour CNO au; p<0.05 vs. saline). Moreover, this marked impairment of glucose tolerance occurred even after a compensatory increase of glucose-induced insulin secretion at the 24 hour time point (Plasma insulin (t=30): 0.42±0.10 for saline vs. 0.45±0.10 ng/mL for 1 hour CNO vs. 1.05±0.20 ng/mL for 24 hour CNO; p=ns). However, despite significant increases in Tc, acute inhibition of POA Pacap+ neurons did not improve glucose tolerance, possibly due to compensation by other WSN populations activated by the thermogenic response. We conclude that POA Pacap+ neurons constitute a subset of WSN that exert profound, previously unrecognized effects on glucose homeostasis. Disclosure J.D. Deem: None. K. Ogimoto: None. K.R. Velasco: None. V. Damian: None. Z. Knight: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S. G.J. Morton: None.