Inhibition of warm sensitive neurons (WSNs) 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 1) WSN inhibition mediates metabolic as well as thermogenic responses to cold, and therefore, 2) WSN activation has the opposite effects. To test this hypothesis, we utilized DREADD technology to activate or inhibit a recently identified subpopulation of POA WSNs defined by their expression of the neuropeptide, Pacap, using the drug clozapine-N-oxide (CNO). We report that, pharmacogenetic activation of this POA WSN population found significant reductions in energy expenditure (Sal vs. CNO: 0.32±0.10 vs. 0.21±0.02 kcal/hr; p<0.05) and, as previously reported, core temperature (Tc) (Sal vs. CNO: 35.4±0.1 vs. 30.4±0.1C; p=0.0001). Further, the response to pharmacogenetic activation was quite long-lived (∼2-3 days) and was accompanied by severe glucose intolerance both 1h and 24h following a single injection of CNO relative to vehicle (glucose AUC: 3610±1216 for Sal vs. 23985±2742 for 1h CNO; 28459±2411 for 24h CNO au; p<0.05 vs. saline), an effect that occurred despite a compensatory increase of glucose-induced insulin secretion at the 24h (but not the 1h) time point (p<0.05 vs. Sal). Thus, activation of POA Pacap+ WSNs is sufficient to reduce thermogenesis and impair glucose tolerance. Conversely, we found that inhibition of POA Pacap+ neurons in chow-fed mice led to a modest but significant increase in Tc (Sal vs. CNO: 35.4±0.1 vs. 35.9±0.1C; p=0.01) and whereas glucose tolerance was not improved in these animals, it was improved by POA Pacap+ neuron inhibition in mice with diet-induced obesity (glucose AUC: 9630±571 for Sal vs. 7517±628 for CNO au; p<0.05). We conclude that POA Pacap+ neurons constitute a subset of WSNs with profound and previously unrecognized effects on glucose homeostasis.


J.D. Deem: None. K. Ogimoto: None. J. Nelson: None. B.N. Phan: 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.


University of Washington Diabetes Research Center

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