Mechanisms of autophagic responses to altered nutritional status.

Autophagy is a dynamic process and critical for cellular remodeling and organelle quality control. In response to altered nutritional status (e.g., fasting and feeding), autophagic activity is finely tuned by transcriptional, posttranslational, and epigenetic regulations via various signaling pathways, including energy sensors (e.g., mechanistic target of rapamycin (mTOR)/ AMP-activated protein kinase - Unc-51 Like Autophagy Activating Kinase 1, mTORC1- WD Repeat Domain, Phosphoinositide Interacting 2, mTORC1- transcription factor EB, perilipin 5- Sirtuin 1, and Sirtuin 1-mediated deacetylation of autophagy proteins), fasting or feeding induced hormones (e.g., fibroblast growth factor [FGF21]- protein kinase A - Jumonji domain-containing protein D3, FGF21- downstream regulatory element antagonist modulator - E3 ligase Midline-1- transcription factor EB, FGF19-SHP- lysine-specific demethylase, insulin- insulin receptor substrate - protein kinase B - forkhead box O, glucagon- protein kinase A - cAMP response binding protein), and lysosomal enzymes (e.g., cathepsin B and cathepsin L). In contrast to fasting that induces autophagy and health benefits, nutrient oversupply (overfeeding or feeding on high energy diets) dysregulates autophagy, which has been increasingly observed in animal models of human chronic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. Studies have revealed multifaceted effects of high energy diets on autophagy, being either an inhibitor or enhancer of autophagy. The conundrum may arise from the variations in methods for autophagy analysis, components of high energy diets and control diets for treatments, treatment durations, and the ages of genetic backgrounds of laboratory animals. In this article, we reviewed the evidence from both human and animal studies, presenting the molecular mechanism of autophagic response to altered nutritional status and discussing the contributing factors of and possible solution to the current conundrum concerning the exact role of high energy diets in autophagic regulation.

Sirt1 coordinates with ERα to regulate autophagy and adiposity.

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.