A Hypothalamic Pathway for Energy Conservation

Many animals utilize a survival strategy of hypothermia, inactivity, and a dramatic decrease in their energy metabolism when faced with a shortfall in energy supplies. Mice, for example, show daily torpor that may last several hours to bridge the lack of energy availability in a cold environment. While our recent studies identified a population of neurons in the median preoptic nucleus (MnPO) necessary for fasting-induced torpor regulation, the specific brain circuits that trigger energy conservation in response to food restriction are unknown. We show here that the energy state of the animal is conveyed to preoptic neurons by inputs from the arcuate nucleus (ARC), a region known to be indispensable for driving metabolic and behavioral adaptations to the fasted state. We first found that the activity of ARC neurons expressing Agouti-Related Peptide (ARCAgRP) is required for the generation of fasting-induced torpor. Then, we showed that torpor-active ARCAgRP neurons innervate the preoptic area of the hypothalamus (POA), including the MnPO. Using optogenetic methods, we also found that activating the ARCAgRP-MnPO pathway induces key features of torpor: decreased body temperature, bradycardia, reduction of energy expenditure, and suppression of brown adipose tissue thermogenesis. Remarkably, we also show that inhibition of the ARCAgRP-MnPO brain circuit entirely prevents fasting-induced torpor. Furthermore, we identified that both NPY and GABA are neuromodulators used by ARCAgRP neurons to enable hypothermic responses during starvation. Our studies provide a detailed view of a hypothalamic pathway enabling energy conservation, a survival mechanism in conditions of low energy availability.