Pregnancy negates thyroid hormone-induced pyrexia

Thyroid hormone (TH) is a key regulator of body temperature; however, its role in the tightly controlled maternal thermoregulatory system that safeguards fetal viability remains unknown. To address this gap, we investigated how maternal hyperthyroidism affects thermoregulation, metabolic tissues, and endocrine signaling in pregnant C57BL/6NCrl mice. Treatment with 3,3',5-triiodo-l-thyronine (T3) from conception to late gestation initially elevated maternal core temperature, reflecting a hypothalamic pyrexic set point. However, this effect was gradually attenuated toward term, permitting the normal prepartum drop in core body temperature. Despite elevated TH levels, brown and white adipose tissues showed no thermogenic activation, whereas skeletal muscle exhibited selective metabolic remodeling, including glycogen depletion and increased mitochondrial capacity in glycolytic muscles, without changes in SERCA2 expression. Notably, maternal T3 treatment further boosted the pregnancy-associated increase in FGF21, whereas adipose tissue remained nonthermogenic, indicating a role of TH-induced FGF21 in sustaining maternal metabolic requirements. Together, these findings reveal a hierarchical adaptation in which central TH effects are overridden, peripheral thermogenic activation is partially suppressed, and endocrine signaling is redirected to maintain maternal-fetal energy balance. In summary, this study identifies a pregnancy-specific mechanism that protects the fetus from hyperthermia while sustaining maternal metabolic demands, with important implications for thyroid dysfunction and fetal programming.NEW & NOTEWORTHY We show that pregnancy attenuates thyroid hormone (TH)-induced pyrexia, consistent with a hierarchical adaptation. This pregnancy-specific mechanism appears to protect the fetus from maternal hyperthermia while redirecting endocrine signaling to meet maternal-fetal energy demands. Importantly, it involves a reprogramming of TH and hepatic FGF21 actions, providing new insights into maternal-fetal energy regulation and the management of thyroid dysfunction during gestation.