Effects of Resveratrol on Browning and Insulin Signaling in Primary Murine Adipocytes: Modulation by Sex and Diabetic Status

<b>Background:</b> Excess accumulation of white adipose tissue is linked to the development of obesity and type 2 diabetes, both of which are associated with systemic metabolic dysfunction. One promising approach is to convert white adipocytes into beige adipocytes, which have greater thermogenic potential and improved insulin sensitivity. Trans-resveratrol (RES), a polyphenolic compound known to have multiple metabolic benefits, has been reported to promote browning of adipocytes and improve insulin signaling; however, it is unclear whether sex and diabetic status modify RES's effects. <b>Methods:</b> We evaluated the ability of RES to induce browning and increase insulin sensitivity in adipose-derived stromal cells (ADSCs) derived from diabetic <i>db</i>/<i>db</i> mice and explored the extent to which these responses are modulated by sex and diabetic status. Subcutaneous ADSCs were isolated from wildtype (WT) and diabetic (<i>db</i>/<i>db</i>) male and female mice and then treated with RES during beige adipocyte differentiation. <b>Results:</b> RES enhanced the expression of <i>Pgc1α</i> and <i>Ucp1</i> mRNA and increased mitochondrial proton leak in ADSCs of both WT and <i>db</i>/<i>db</i> mice. RES also enhanced insulin-induced AKT phosphorylation in all groups of ADSCs. Notably, the effects of RES on browning and insulin signaling were influenced by the sex and diabetic status of the mice, as ADSCs from female diabetic mice responded differently compared with those from their WT or male counterparts. <b>Conclusions:</b> These findings highlight the importance of considering sex and diabetic status when developing browning strategies to target obesity and type 2 diabetes.