<i>Abcc1</i> deficiency protects from corticosterone but not cortisol‐induced adiposity and insulin resistance in a sex‐specific manner

Exogenous glucocorticoid (GC) therapy, whether physiological replacement in adrenal insufficiency or pharmacological treatment of inflammatory diseases, confers significant cardiometabolic risks, including obesity and insulin resistance. Finding safer alternative GCs is thus a pressing goal. Corticosterone, a minor endogenous GC in humans, may have fewer deleterious metabolic effects than cortisol (hydrocortisone), potentially mediated through selective export via the Abcc1 transporter. In adrenalectomised mice we compared oral corticosterone and cortisol administration and investigated whether Abcc1 mediates differential metabolic effects, and whether such responses are sexually dimorphic. After an initial dose-response study male and female Abcc1-knockout (Abcc1^-/-) and wild-type (WT) mice were administered corticosterone or cortisol (25 µg/mL) in drinking water for up to 5 weeks. Cortisol induced greater insulin resistance and elevated energy expenditure compared to corticosterone, an effect more pronounced in male mice. Corticosterone-treated Abcc1^-/- males, surprisingly, exhibited reduced fat mass and improved insulin sensitivity compared to WT controls. This protective effect of Abcc1 deficiency was neither observed in cortisol-treated mice nor in female mice receiving either treatment. These findings confirm that even at relatively low doses cortisol drives more severe metabolic dysregulation than corticosterone, independent of Abcc1. Paradoxically Abcc1 deletion protects against corticosterone-induced adiposity in males. Moreover sex modulates GC responses. These findings challenge the presumed role of Abcc1 in GC export and highlight the importance of sex in GC action. Together these results underscore corticosterone's potential as a safer GC therapy, advance our understanding of sex-specific GC action and raise novel questions about Abcc1's role in GC regulation. KEY POINTS: Current glucocorticoid therapies carry significant cardiometabolic risks, including obesity and insulin resistance, highlighting the need for safer alternatives. Corticosterone may have fewer harmful metabolic effects than cortisol, hypothesised to result from its selective export from cells by the Abcc1 transporter. In a mouse model of exogenous glucocorticoid excess cortisol induced more severe insulin resistance and increased energy expenditure compared to corticosterone, but only in male mice. Unexpectedly Abcc1-knockout males treated with corticosterone showed reduced fat mass and improved insulin sensitivity, an effect not seen with cortisol or in females. These results challenge the assumed role of Abcc1 in glucocorticoid export, highlight sex differences in glucocorticoid action and support corticosterone's potential as a safer therapeutic option.