Pangas, S. A. | bioRxiv Science

bioRxiv2025

Beige fat appearance during lipoatrophy reveals trade-offs between metabolic homeostasis and female fertility

White adipose tissue (WAT) meets the energetic demands required for estrous cycle regularity, ovulation, and reproductive success in women. Here, we report WAT loss and subsequent female-specific compensatory beige fat recruitment impact metabolic and reproductive outcomes in mice. Female mice that undergo progressive lipoatrophy ( fat-less) displayed disrupted estrous cycles, reduced ovarian reserve, and subfertility. These effects were attributable to an accumulation of thermogenic beige fat cells in residual subcutaneous WAT depots and greater energy expenditure. Conversely, high-fat diet lowered energy expenditure and rescued estrous cycle regularity among fat-less mice compared to littermate controls, despite profound insulin resistance and metabolic dysfunction. Together, these findings provide evidence of trade-offs between the maintenance of metabolic homeostasis and reproduction, where increased energy expenditure and beige fat cell emergence compensate for fat loss but occur at the expense of fecundity in female mice.

cell biology↗

bioRxiv2020

Ubc9 deletion in adipocytes causes lipoatrophy in mice

ObjectiveWhite adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2-conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions of Ubc9 frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown. MethodsTo determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specific Ubc9 knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ubc9 locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion of Ubc9 in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ubc9a-KO and littermate controls during postnatal growth. ResultsTo our surprise, Ubc9a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period. ConclusionsOur results demonstrate that Ubc9 expression in mature adipocytes is essential for maintaining WAT expansion. Deletion of Ubc9 in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ubc9 during white adipocyte expansion and endocrine control of energy balance.

developmental biology↗