Abstract Body (Do not enter title and authors here): Introduction: Obesity is a major risk factor for various diseases and the clinical manifestations of obesity vary between sexes.Studies have shown that DIO induces GDF15 levels in various tissues including liver and BAT. However; whether BAT-derived GDF15 contributes to serum levels and mediates changes to energy homeostasis during DIO had not been tested.

Research Questions/Hypothesis: Here, we tested the hypothesis that BAT-derived GDF15 regulates systemic metabolism during DIO in male and female mice.

Methods/Approach: We generated mice with selective Gdf15 deletion in thermogenic adipocytes by crossing Gdf15 floxed mice with mice harboring the Cre recombinase under the control of the Ucp1 promoter (GDF15 BKO mice). Male and female GDF15 BKO mice were subjected to 12 weeks of HFD feeding (60% calories from fat), after which we assessed changes in body weight, body composition, metabolic rates, glucose homeostasis and insulin sensitivity. Global transcriptomic analysis was performed in BAT of male and female mice to shed light on molecular mechanisms and ovariectomy studies were performed to assess the effects of sex-steroid hormones on the metabolic phenotype of female mice.

Results: GDF15 BKO male mice had increased food intake and were more susceptible to DIO, with higher weight gain and fat mass accumulation. Conversely, female KO mice had reduced food intake and increased resting metabolic rates leading to resistance to DIO. Importantly, these effects were blunted in ovariectomized mice. Sex-genotype interaction analysis of RNASeq data in BAT identified genes conversely regulated by Gdf15 deletion in females vs. males. Cyp2e1, was one of the top 20 genes identified and was highly induced in females, while repressed in males. Cyp2e1 induction in BAT was prevented in ovariectomized KO female mice, suggesting a role for sex-steroid hormones in Cyp2e1 regulation. Moreover, DIO significantly increased Cyp2e1 levels in BAT of female WT mice, whereas Cyp2e1 levels are unchanged in males, indicating that diet alone might regulate Cyp2e1 expression in BAT in a sex-dependent manner.

Conclusions: Our data revealed that GDF15 deletion in BAT regulates energy homeostasis in a sex-dependent manner and suggests a role for Cyp2e1 induction in promoting metabolic protection in female mice under DIO conditions. Future studies in mice with selective deletion of Cyp2e1 in BAT should shed light on its role in BAT function and systemic metabolism across sexes.