A Preoptic Neurocircuit that Regulates Blood Glucose Homeostasis

Abstract

The preoptic area (POA) is the core thermoregulatory center of all known endothermic species and balances heat generation and cooling in response to environmental stimuli. This delicate balance is executed via a brain-body exchange of sensory information and thermoregulatory output that is intimately connected to the nutritional state of the organism. When faced with food deprivation, certain endotherms engage in torpor, a behavior in which body temperature and metabolic rate are substantially depressed to improve the probability of organismal survival. Induction of torpor is regulated by anteroventral POA (avPOA) Vglut2⁺/Adcyap1⁺ neurons, which are necessary and sufficient to induce this state. How these neurons regulate the metabolic depression observed during torpor remains poorly understood. In this work, we show that activation of avPOA_Vglut2/PACAP neurons results in temperature-independent changes in whole-body changes in fuel usage, from glucose to fatty acids, driven predominantly via insulin signaling defects in skeletal muscle. This metabolic shift is executed via engagement of the hypothalamic-pituitary-adrenal axis, and impairment of this process via silencing of avPOA_Vglut2/PACAP neurons results in a loss of fasting glucose homeostasis. Taken together these results nominate torpor-associated avPOA_Vglut2/PACAP neurons as core regulators of glucose homeostasis, and provide a basis for understanding how endotherms utilize hierarchical control of metabolism to tune energy expenditure and survive extreme periods of energetic deprivation.