Time-controlled fasting prevents high fat diet-induced metabolic inflexibility in skeletal muscle.

<p>(A) High fat diet causes a massive flux of fatty acids into skeletal muscle cells triggering an uncontrolled mitochondrial oxidative metabolism. A persistence of such dietary pattern induces a decrease of Atgl and metabolic inflexibility in skeletal muscle causing elevation of circulating levels of glucose, lipids and insulin. The occurrence of such systemic metabolic gridlock might be the consequence of a protective response (insulin resistance) of metabolically exhausted cells (aging phenotype). (B) Cycles of time-controlled fasting (>24h) boosts mitochondrial oxidative metabolism in skeletal muscle that confers an adaptive stress resistance to nutrient fat overload. Under fasting, the induction of Atgl represents the key molecular event that promotes a controlled release and gradual oxidation of fatty acids into mitochondria. These adaptive responses result in an effective metabolic flexibility preventing high fat diet-induced aging phenotype (geroprotection).