SUN-636 ‘Fatless’ Mice Reveal Fundamental Aspects of Adipose Tissue Requirements for Female Reproduction

Abstract Disclosure: E.S. Anaya: None. S.K. Pradip: None. J. Lydon: None. S.A. Pangas: None. S.M. Hartig: None. Across the female reproductive cycle, dynamic shifts in energy expenditure, insulin sensitivity, and lipid metabolism occur in accordance with the rise and fall of sex steroid hormones. The ability to store and mobilize energy efficiently is imperative for female reproduction and thus requires tight coordination between metabolic and reproductive tissues. Consequently, overweight and underweight women have a greater risk of menstrual irregularities, ovulatory disorders, and reduced fertility treatment success. To understand how adipose tissue competence contributes to female fertility, we used a novel mouse model of lipodystrophy containing an adipose tissue-specific knockout of Ubc9 (Ubc9fKO) previously generated in our laboratory. However, contrary to our expectations, these lipodystrophic mice have abnormal yet cyclical estrous cycles and the ability to produce progeny until six months of age. Upon further analysis of the residual sWAT, we noticed sex-specific increases in UCP1+ multilocular adipocytes in young knockout females, corresponding to increased beige fat gene expression. Although infertility and amenorrhea are often seen as a result of lipodystrophy, we hypothesize that the emergence of beige fat in the absence of competent white adipocytes may maintain the metabolic and endocrine functions needed for pregnancy and parturition in these mice. Supporting this concept, in female WT mice, we observed estrous cycle-dependent morphological changes in adipocyte size, the presence of UCP1+ multilocular adipocytes, and alterations in beige fat gene expression both in vivo and in vitro. Our analysis of WAT in Ubc9fKO and WT mice suggests an unappreciated and important role for beige fat in metabolic regulation during mouse estrous cycling. Importantly, this research addresses the emphasis on women’s health, underscoring the importance of studying sex-specific differences in metabolism. Presentation: Sunday, July 13, 2025