Hypothalamic thyroid hormone deficiency underlies reversible anorexia in a mammalian hibernator

Mammalian hibernators survive prolonged periods of cold and resource scarcity by temporarily modulating normal physiological functions, but the mechanisms underlying these adaptations are poorly understood. The hibernation cycle of thirteen-lined ground squirrels lasts for 5–7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24–48-hour periods of an active-like interbout arousal (IBA) state. We show that ground squirrels, who endure the entire hibernation season without food, have negligible hunger drive during IBAs. We further demonstrate that squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons have reduced sensitivity to the orexigenic and anorexigenic effects of ghrelin and leptin, respectively. However, hypothalamic infusion of thyroid hormone during an IBA is sufficient to rescue hibernation anorexia. Our results reveal that thyroid hormone deficiency underlies hibernation anorexia and demonstrate the functional flexibility of the hypothalamic feeding center. Overall design: Single cell gene expression in the arcuate nucleus of hypothalamus and median eminence was compared between active and hibernating thirteen-lined ground squirrels by single cell RNA sequencing on the 10X Genomics platform