Leptin counteracts hypothermia in hypothyroidism through its pyrexic effects and by stabilizing serum thyroid hormone levels.

Abstract Objective Thyroid hormones (TH) are essential for the homeostatic control of energy metabolism and the regulation of body temperature. The hypothalamic-pituitary-thyroid (HPT) axis is regulated by negative feedback mechanisms ensuring that TH levels are maintained at a constant level. However, the feedback mechanisms underlying the resetting of HPT axis regulation in the control of body temperature are still not fully understood. Here, we aimed to determine the thermoregulatory response in hypothyroid mice to different environmental temperatures and the underlying mechanisms. Methods Distinct thermogenic challenges were induced in hypothyroid female C57BL/6N and leptin-deficient ob/ob mice through housing at either room temperature or thermoneutrality. Thermogenic and metabolic effects were analyzed through metabolic chambers, 18F-FDG-PET/MRI, infrared thermography, metabolic profiling, histology, gene expression and Wester Blot analysis. Results In hypothyroid mice maintained at room temperature, high leptin serum levels induce a pyrexic effect leading to the stabilization of body temperature through brown adipose tissue thermogenesis and white adipose tissue browning. Housing at thermoneutrality leads to a normalization of leptin levels and a reduction of the central temperature set-point resulting in decreased thermogenesis in brown and white adipose tissue and skeletal muscle and a significant decline in body temperature. Furthermore, anapyrexia in hypothyroid leptin deficient ob/ob mice indicates that besides its pyrexic actions, leptin confers a stimulatory effect on the HPT axis to stabilize remaining TH serum levels in hypothyroid mice. Conclusion This study led to the identification of a previously unknown endocrine loop in which leptin acts in concert with the HPT axis to stabilize body temperature in hypothyroid mice.