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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 (Ictidomys tridecemlineatus) lasts for 5–7 months and comprises weeks of hypometabolic, hypothermic torpor interspersed with 24–48-h 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 during IBAs. These squirrels exhibit reversible inhibition of the hypothalamic feeding center, such that hypothalamic arcuate nucleus neurons exhibit 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. 

Thriving in times of resource scarcity requires an incredible flexibility of behavioral, physiological, cellular, and molecular functions that must change within a relatively short time. Hibernation is a collection of physiological strategies that allows animals to inhabit inhospitable environments, where they experience extreme thermal challenges and scarcity of food and water. Many different kinds of animals employ hibernation, and there is a spectrum of hibernation phenotypes. Here, we focus on obligatory mammalian hibernators to identify the unique challenges they face and the adaptations that allow hibernators to overcome them. This includes the cellular and molecular strategies used to combat low environmental and body temperatures and lack of food and water. We discuss metabolic, neuronal, and hormonal cues that regulate hibernation and how they are thought to be coordinated by internal clocks. Last, we touch on questions that are left to be addressed in the field of hibernation research. Studies from the last century and more recent work reveal that hibernation is not simply a passive reduction in body temperature and vital parameters but rather an active process seasonally regulated at the molecular, cellular, and organismal levels.