TY - JOUR
T1 - Leptin counteracts hypothermia in hypothyroidism through its pyrexic effects and by stabilizing serum thyroid hormone levels
AU - Weiner, Juliane
AU - Roth, Lisa
AU - Kranz, Mathias
AU - Brust, Peter
AU - Boelen, Anita
AU - Klöting, Nora
AU - Heiker, John T.
AU - Blüher, Matthias
AU - Tönjes, Anke
AU - Pfluger, Paul T.
AU - Stumvoll, Michael
AU - Mittag, Jens
AU - Krause, Kerstin
N1 - Funding Information: This work was funded by grants of the Deutsche Forschungsgemeinschaft (KR 4258/1-1 and KR 4258/3-1 to KK, TO 718/2-1 to AT and SFB1052 (B1 to MB, B4 to NK, C7 to JW and JTH) and by the HI-MAG funding for the project ?Modulation of peripheral thyroid hormone function by CNS leptin action ? of the Medical Faculty of the University Leipzig and the Helmholtz Zentrum M?nchen. Funding Information: This work was funded by grants of the Deutsche Forschungsgemeinschaft ( KR 4258/1-1 and KR 4258/3-1 to KK, TO 718/2-1 to AT and SFB1052 (B1 to MB, B4 to NK, C7 to JW and JTH) and by the HI-MAG funding for the project "Modulation of peripheral thyroid hormone function by CNS leptin action " of the Medical Faculty of the University Leipzig and the Helmholtz Zentrum München . Publisher Copyright: © 2021 The Author(s)
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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 the 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. The thermogenic and metabolic effects were analyzed through metabolic chambers, 18F-FDG-PET/MRI, infrared thermography, metabolic profiling, histology, gene expression and Western 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 the 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 exerts a stimulatory effect on the HPT axis to stabilize the 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.
AB - 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 the 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. The thermogenic and metabolic effects were analyzed through metabolic chambers, 18F-FDG-PET/MRI, infrared thermography, metabolic profiling, histology, gene expression and Western 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 the 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 exerts a stimulatory effect on the HPT axis to stabilize the 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.
KW - Beige adipose tissue
KW - Brown adipose tissue
KW - Leptin
KW - Thermogenesis
KW - Thyroid hormone
KW - White adipose tissue browning
UR - http://www.scopus.com/inward/record.url?scp=85117837624&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.molmet.2021.101348
DO - https://doi.org/10.1016/j.molmet.2021.101348
M3 - Article
C2 - 34610354
SN - 2212-8778
VL - 54
JO - Molecular metabolism
JF - Molecular metabolism
M1 - 101348
ER -