Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates

Calorie restriction (CR) increases longevity and retards the development of many chronic diseases, but the underlying metabolic signals are poorly understood. Increased fatty acid (FA) oxidation and reduced FA synthesis have been hypothesized to be important metabolic adaptations to CR. However at steady state, FA oxidation must match FA intake plus synthesis; FA intake is low, not high, during CR. It is therefore not clear how FA dynamics are altered during CR. Accordingly, we measured food intake patterns, whole‐body fuel selection, endogenous FA synthesis and gene expression in mice on CR. Within two days of starting CR, a shift occurred to a cyclic pattern of whole‐body FA metabolism, with an initial phase of elevated endogenous FA synthesis (respiratory exchange ratio [RER]>1.10, lasting 4–6 hours after food provision), followed by a prolonged phase of FA oxidation (RER=0.70, lasting 18–20 hours). CR mice oxidized four times as much fat per day as ad libitum fed (AL) controls (367 vs 97 mg/d) despite reduced fat intake. This increase in FA oxidation was balanced by a 3‐fold increase in adipose tissue FA synthesis. We conclude that CR induces a surprising metabolic pattern characterized by periods of elevated FA synthesis alternating with periods of FA oxidation disproportionate to dietary FA intake. This pattern may have implications for understanding the reduced oxidative damage and disease risk in CR animals. Grant Funding Source: NIH