Endocrine Abstracts

Although obesity affects men and women, the risks of associated metabolic disturbances (e.g. type 2 diabetes) differ between the sexes. Altered peripheral glucocorticoid metabolism may underpin the metabolic consequences of obesity; however, most research exploring this has focused on male animals. This study used a mouse model to investigate the hypothesis that alterations in glucocorticoid metabolism caused by diet-induced obesity (DIO) will be more profound in males than in females.

Male and female C57Bl/6 mice were fed obesogenic or control diets (for 8 weeks) from weaning (n=8/group) and underwent metabolic testing. Enzyme activity and mRNA expression were quantified from snap frozen tissues obtained post-mortem.

After 8 weeks, DIO mice were heavier than controls and displayed hyperglycaemia and hyperinsulinaemia: these changes were more severe in males. In DIO males, peak corticosterone levels were decreased (DIO 310.6±30.9 versus Con 509.4±66.6, P<0.05) and hepatic expression of 5-β reductase (5βr) and 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1; DIO 1.27±0.10 versus Con 0.92±0.11, P<0.05) were increased. In contrast, in DIO females, peak corticosterone levels were increased (DIO 1017±127.7 versus Con 488.0±75.3, P<0.01), whilst hepatic expression (DIO 0.83±0.06 versus Con 1.43±0.04, P<0.001) and activity of 11βHSD1 were decreased. Furthermore, hepatic 5βr expression was decreased whereas 5-α reductase expression was increased. DIO in males was also associated with decreased adipose 11βHSD1 expression, while no such changes were seen in females.

These results indicate that increased 5βr in male mice with DIO is responsible for decreased circulating corticosterone whilst increased 11βHSD1 activity maintains intrahepatic concentrations. The opposite is seen in females, in which decreased 11βHSD1 may compensate for increased systemic corticosterone. Thus, DIO induces sex-dependent changes in the hypothalamic–pituitary–adrenal axis and glucocorticoid metabolism. We suggest that such sexually dimorphic effects may play a role in the differential metabolic responses to obesity in males and females.