Sex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.

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Skeletal muscle atrophy is a physiological condition that is caused by a myriad of conditions, including immobilization, denervation, spinal cord injury and corticosteroid use and results in decreased muscle size and strength. The molecular genetic events of neurogenic atrophy were analyzed in a previous study using gastrocnemius muscle isolated from mice following 3 days and 14 days of denervation. The gene expression profile in the denervated muscle tissue was analyzed by microarray and compared to control muscle tissue to identify novel genes that are differentially expressed in response to neurogenic atrophy. The microarray data revealed for the first time that F‐box and WD‐40 Domain Protein 5 (Fbxw5) and F‐box Protein 44 are expressed in skeletal muscle and are differentially regulated in response to denervation. Fbxw5 and Fbxo44 are classified as E3 ubiquitin ligases and both have been found to interact with cullin 4 and DNA damage binding protein 1 (DDB1) complexes. Furthermore, Fbxo44 has been found to ubiquitinate and destabilize both BRCA1 and regulator of G protein signaling 2 (RGS2), while Fbxw5 has been shown to destabilize DLC1, a RhoA GTPase‐activating protein, and tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR. To confirm that Fbxw5 and Fbxo44 are expressed in muscle, quantitative PCR (qPCR) was used to assess the expression levels of these two E3 ligases in both proliferating and differentiated muscle cells and the results demonstrate that expression levels appear to remain relatively constant in proliferating myoblasts and differentiated myotubes. Furthermore, Western blot analysis supported the qPCR data and showed that Fbxw5 and Fbxo44 protein levels remain relatively constant as cultured myoblasts differentiate to myotubes. The discovery that Fbxw5 and Fbxo44 are expressed in skeletal muscle and are differentially regulated in response to neurogenic atrophy helps further our understanding of the molecular genetic events of muscle wasting and may eventually lead to the identification of new therapeutic targets for the treatment and prevention of atrophy.Support or Funding InformationThe work was support by University of North Florida Transformational Learning Opportunity grants and a University of North Florida Foundation Board Grant to D.W.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.