A mouse model of lipoatrophy reveals relationships between beige fat appearance and female fertility

Abstract White adipose tissue (WAT) performs vital metabolic and endocrine functions, but roles in female reproduction remain understudied and poorly understood. Here, we report that female mice experiencing progressive lipoatrophy after knockout of Ubc9 in adipocytes (Ubc9fKO) displayed disrupted estrous cycles, reduced ovarian reserve, and subfertility. During aging, female Ubc9fKO mice lose subcutaneous WAT more quickly than their male counterparts and weigh less than littermate controls. Subcutaneous WAT excised from female Ubc9fKO mice strongly enriched for thermogenesis genes generally associated with metabolic benefits. Female Ubc9fKO mice exhibited hypermetabolism and accumulated thermogenic, Uncoupling Protein 1 (UCP1)-expressing beige fat cells in residual subcutaneous WAT depots in a sex-dependent manner. However, remnant beige fat appearance occurred at the expense of fertility in Ubc9fKO female mice. A high-fat diet diminished the appearance of beige fat cells and restored estrous cycle regularity among Ubc9fKO mice compared to littermate controls, despite the presence of profound insulin resistance. Together, these results reveal sexual dimorphism in a mouse model of lipoatrophy and the importance of WAT for sustaining reproduction in female mice. These findings also provide evidence that beige adipocytes compensate for fat loss at the expense of fecundity in female mice and identify pathways to improve fertility in very lean and lipodystrophic women.