SAT-660 - Brown Adipose Tissue–Specific Deletion of Cyp2e1 Reveals a Novel Sex Dependent Regulator of Thermogenesis and Metabolic Homeostasis

Background:
Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and systemic metabolic regulation, yet the mechanisms driving sex specific BAT function remain incompletely understood. Cytochrome P450 2E1 (CYP2E1), an enzyme classically associated with hepatic xenobiotic and ethanol metabolism, is expressed in specific thermogenic adipocyte populations, but its role in BAT thermogenesis and BAT mediated metabolic control has not been previously examined.

Method:
Newly generated male and female mice with BAT specific deletion of Cyp2e1 (KO) and littermate controls were studied following chow (n=22-29), high fat diet (HFD; 16 weeks; n=5-13), and cold exposure (n=4-14). Body weight, body composition, fasting glucose and insulin, glucose tolerance tests (GTTs), insulin tolerance tests (ITTs), and core body temperature were assessed. Male and female data were disaggregated for analysis and significant differences were determined by Student’s t-test using a significance level of p< 0.05.

Results:
Under chow conditions, male KO mice exhibited reduced body weight and fat mass, despite mildly elevated fasting glucose and preserved glucose tolerance. Female KO mice showed impaired glucose tolerance without changes in body composition. Following HFD feeding, body weight, adiposity, and fasting insulin were unchanged by genotype in both sexes. However, male KO mice developed impaired insulin tolerance, whereas female KO mice demonstrated modestly improved insulin sensitivity. During cold exposure, male KO mice displayed increased core body temperature, indicating enhanced BAT thermogenic function, while females were largely unaffected.

Conclusion:
BAT CYP2E1 functions as a sex and context dependent metabolic modulator. In chow fed males, CYP2E1 expression restrains BAT thermogenesis and energy homeostasis, whereas under HFD conditions it is required to limit insulin resistance. Females lacking BAT CYP2E1 are largely refractory to thermogenic effects but benefit from improved insulin sensitivity during obesity. These findings reveal a previously unrecognized dual role for BAT CYP2E1 linking nutritional state and sex to thermogenic and glucose regulatory pathways.

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