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

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 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.