When food resources are scarce, endothermic animals can lower core body temperature (Tb). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrus-specific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent Tb regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway. Significance Energy homeostasis is fundamental for the survival of living organisms and contributes to their health, longevity, and aging. When food resources are scarce, and during experimental calorie restriction, endothermic animals can lower their core body temperature. Here, we found that this response is regulated by the insulin-like growth factor 1 receptor. This demonstrates that the three main factors affecting aging and longevity (calorie restriction, reduction of the insulin-like growth factor 1 signaling, and lowered temperature) are components of the same pathway that modulates energy homeostasis. The finding also identifies body temperature reduction as a common determinant of the effects of both calorie restriction and reduced insulin-like growth factor 1 receptor signaling.
Figure: Effect of CR on Tb in neuron-specific IGF-1R knockout (inIGF1RKO)