Impaired maternal thyroid hormone receptor A1 signaling programs offspring metabolism

Maternal-fetal programming occurs during pregnancy and lactation and leads to epigenetic changes in the physical structure of DNA with life-long effects on the offspring. Thereby, maternal factors, such as nutrients and hormones, have considerable impact on the development of embryos and can, already in the prenatal stage, increase the risk for the development of metabolic We here show that impaired maternal thyroid hormone receptor alpha1 signaling induces changes in the fetal programming of the offspring metabolic set point. Using female mice harboring a mutation in thyroid hormone receptor alpha1 (TRalpha1+m mice) as dams, we observed that their male offspring displayed a normal early postnatal development but showed a reduction in body weight later during adulthood. Furthermore, animals showed a faster glucose clearance and improved insulin sensitivity. To test whether the cause of this beneficial metabolic phenotype could be maternal hypermetabolism due to overactivated brown adipose tissue of TRalpha1+m mice, we pharmacologically mimicked a situation of elevated maternal thermogenesis and hypermetabolism. Therefore, we treated female wild type mice with prazosin (50 mug/ml oral), a alpha-adrenergic antagonist that is commonly used for the treatment of hypertension, during pregnancy and lactation. Prazosin treatment enforced heat loss over the tail surface by decreasing the sensitivity of tail arteries to contractile stimuli, thereby stimulating facultative thermogenesis and metabolism. Interestingly, male offspring of prazosin-treated dams showed a similar reduction in body weight as male offspring of TRalpha1+m dams. However, their glucose clearance was remarkably reduced as animals were suffering from an insulin resistance. Taken together, although the underlying mechanism of fetal programming by maternal thyroid hormone signaling needs further investigation, our results clearly demonstrate the complexity and particular importance of thyroid hormone for fetal programming of metabolic diseases.