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Single housing induces behavioral, neuroendocrine and metabolic alterations. As thyroid hormones (TH) regulate several aspects of metabolism, and HPT axis is modulated by energy status and emotional stress, we evaluated the effect of isolation on HPT axis response to a palatable diet under basal conditions and after an acute stressor as restraint. Weaned female or male rat pups (Wistar) were caged alone (isolated, Iso; n=8) or in groups of 4 (group housed, Gh; n=12) at postnatal day (PND) 22. At adulthood (PND 63), Gh and Iso rats had access to chow or a palatable diet (Pd: peanuts, cookies, chow) for 1 or 3 months and exposed, in the latter, to 1 h of restraint stress (RES). Gh or Iso males and females increased their kcal intake of Pd, inducing white fat (WAT) accumulation (more in females), leptinemia and insulinemia. Pd for1 month increased Trh -degrading enzyme expression in both Gh sexes, and decreased TSH in Gh males. In females, T4 increased in Gh-Pd; TSH and T4 reduced in Iso-Pd rats. After 3 months of Pd, RES activated adrenal axis, but its response was curtailed by Pd in Gh-males, and to a lesser extent in Iso. In Gh-Pd females, corticosterone decreased but not in Iso. RES-induced inhibition of HPT axis was not diminished by Pd in Gh-males, as seen in the adrenal response, on the contrary, it decreased even further to a similar extent as did Iso in Trh expression, TSH and T4 levels; Iso reduced T3 levels independent of diet. In females, the only significant change was an increase in Trh mRNA levels in Iso-chow. Brown adipose tissue (BAT) gene expression was affected in Gh and Iso males by Pd ( Adrb3 and Dio2 ) whereas in females, Dio2 decreased only in Iso-Pd. These results support a differential adrenal and HPT responses due to sex and housing. HPT axis activity increases by energy demands, we thus studied the effect of 2 weeks of voluntary wheel running (WR) in Gh and Iso adult rats. Controls were sedentary (Sed) pair-fed to the amount of food consumed by WR groups. Females ran more than males and, in either sex, Gh and Iso ran equivalently. WR reduced body weight gain in Iso and Gh males, without changes in fat mass. Gh females lost body weight, but not Iso; ovaric and subcutaneous fat decreased in Gh rats, Iso only lost subcutaneous fat. WR diminished PVN Trh mRNA levels and increased serum TSH in female Gh. Iso blunted several TH- and exercise-induced targets in BAT and WAT. WR stimulated BAT expression of Adrb3 and Ucp1 in Gh or Iso males whereas in Iso females, Dio2 and Ucp1 . WR increased Adrb3 in WAT of Gh males or females and Pparg in Gh males and in Iso females. These results show the complex and multifactorial modulation of metabolism between males and females. In conclus...