Sex Dimorphic Changes in Trh Gene Methylation and Thyroid-Axis Response to Energy Demands in Maternally Separated Rats

Abstract

Abstract The hypothalamus-pituitary-thyroid (HPT) axis regulates energy balance through the pleiotropic action of thyroid hormones. HPT basal activity and stimulation by cold or voluntary exercise are repressed by previous chronic stress in adults. Maternal separation (MS) modifies HPT basal activity; we thus studied the response of the axis to energy demands and analyzed possible epigenetic changes on Trh promoter. Nonhandled (NH) or MS male Wistar rats were cold exposed 1 h at adulthood; Trh expression in the hypothalamic paraventricular nucleus (PVN) and serum thyrotropin (TSH) concentration were increased only in NH rats. Two weeks of voluntary exercise decreased fat mass and increased Trh expression, and thyroid hormones concentration changed proportionally to running distance in NH male rats and MS male rats. Although NH females ran more than MS and much more than males, exercise decreased body weight and fat mass only in NH rats with no change on any parameter of the HPT axis but increased Pomc expression in arcuate-nucleus of NH and Npy in MS females. Overall, the methylation pattern of PVN Trh gene promoter was similar in NH males and females; MS modified methylation of specific CpG sites, a thyroid hormone receptor (THR)-binding site present after the initiation site was hypomethylated in MS males; in MS females, the THR binding site of the proximal promoter (site 4) and 2 sites in the first intron were hypermethylated. Our studies showed that, in a sex-dimorphic manner, MS blunted the responses of HPT axis to energy demands in adult animals and caused methylation changes on Trh promoter that could alter T3 feedback.