Mechanisms of autophagic responses to altered nutritional status

Abstract

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.

Keywords: Autophagy; Epigenetics; Fasting; High energy diet; Metabolism; Nutritional status; Overfeeding.