Sexual dimorphism of liver endoplasmic reticulum stress susceptibility in prepubertal rats and the effect of sex steroid supplementation.

New Findings: What is the central question of this study? Is there sexual dimorphism in the occurrence of hepatic endoplasmic reticulum stress? What is the main finding and its importance? The transition from prepubertal to the adult age is associated with an increase in the unfolded protein response markers in the liver of male rats, which is probably due to an increase in serum testosterone levels.

Abstract: Male rodents present a higher predisposition to obesity and insulin resistance than females. These disorders have been associated with endoplasmic reticulum (ER) stress. To investigate a possible sexual dimorphism in the hepatic occurrence of ER stress, we evaluated the expression of ER stress markers in the livers of male and female rats in two phases of sexual development. In the first experimental model, male and female prepubertal and adult Wistar rats were used. Adult males presented higher body mass and greater mass of the adipose tissue and liver than adult females. Prepubertal animals presented no differences in these parameters between males and females. Despite this finding, the hepatic expression levels of Bip, Ire1α and Xbp1s mRNA were lower in prepubertal males than in females, while in adult animals, they did not differ between sexes. In the second experimental model, we anticipated the sexually mature phase by daily injections of testosterone propionate for 10 days in prepubertal males or by daily injections of oestradiol benzoate for 7 days in prepubertal females. Oestradiol administration in prepubertal females did not change any of the parameters evaluated. Testosterone administration to prepubertal males led to a higher body mass and greater expression of Bip, Ire1α, Atf4 and Xbp1s in the liver. These findings suggest that the increased ER stress predisposition observed in males during puberty is due to an increase in testosterone levels, indicating that ER stress is sexually dimorphic before puberty due to the lack of testosterone in males.