Glucoregulatory responses to hypothalamic preoptic area cooling

Abstract

Normal glucose homeostasis depends on the capacity of pancreatic β-cells to adjust insulin secretion in response to a change of tissue insulin sensitivity. In cold environments, for example, the dramatic increase of insulin sensitivity required to ensure a sufficient supply of glucose to thermogenic tissues is offset by a proportionate reduction of insulin secretion, such that overall glucose tolerance is preserved. That these cold-induced changes of insulin secretion and insulin sensitivity are dependent on the sympathetic nervous system (SNS) outflow suggests a key role for thermoregulatory neurons in the hypothalamic preoptic area (POA) in this metabolic response. As these POA neurons are themselves sensitive to changes in local hypothalamic temperature, we hypothesized that direct cooling of the POA would elicit the same glucoregulatory responses that we observed during cold exposure. To test this hypothesis, we used a thermode to cool the POA area, and found that as predicted, short-term (8-h) intense POA cooling reduced glucose-stimulated insulin secretion (GSIS), yet glucose tolerance remained unchanged due to an increase of insulin sensitivity. Longer-term (24-h), more moderate POA cooling, however, failed to inhibit GSIS and improved glucose tolerance, an effect associated with hyperthermia and activation of the hypothalamic-pituitary-adrenal axis, indicative of a stress response. Taken together, these findings suggest that POA cooling is sufficient to recapitulate key glucoregulatory responses to cold exposure.