Ash2l deficiency impairs adipose tissue thermogenesis and exacerbates obesity in mice

Epigenetic regulation plays a pivotal role in adipocyte development and thermogenesis. Ash2l, a key component of the COMPASS (Complex of Proteins Associated with Set1) histone methyltransferase, regulates gene expression through epigenetic mechanisms. This study explored the role of Ash2l in adipose tissue thermogenesis and obesity-related metabolic dysfunction. Ash2l was initially identified through transcriptomic analysis, and its expression was further validated in mouse models of high-fat diet (HFD), cold exposure, and CL316,243 stimulation. In vitro gain- and loss-of-function experiments were conducted to assess the role of Ash2l in adipogenesis and thermogenesis. To knockdown Ash2l in vivo, adeno-associated viruses carrying short hairpin RNA targeting Ash2l (AAV-shAsh2l) were injected into either the brown adipose tissue (BAT) or the inguinal white adipose tissue (iWAT). The functional consequences of Ash2l deficiency were evaluated in mice under room temperature, cold exposure, and HFD conditions. Finally, chromatin immunoprecipitation sequencing (ChIP-seq) was employed as an exploratory analysis to identify genomic regions associated with Ash2l during adipocyte development. Our findings demonstrate that Ash2l modulates the expression of both adipogenic and thermogenic genes in adipocytes. Mice with BAT- or iWAT-knockdown of Ash2l displayed defective cold-induced thermogenesis, aggravated diet-induced obesity, and systemic metabolic dysregulation. Moreover, Ash2l knockdown in BAT under cold exposure or HFD conditions also attenuated thermogenic activity in iWAT, an effect that may be mediated by reduced secretion of FABP4. These findings establish Ash2l as a critical regulator of adipogenesis and thermogenesis. This study provides important insights into the epigenetic role of Ash2l in maintaining metabolic homeostasis under conditions of nutritional excess.