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RESEARCH ARTICLE

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

¹University of California, Berkeley ²Children's Hospital Oakland Research Institute

Submitted 25 August 2009 ; revised 2 November 2009 ; accepted in final form 2 November 2009

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. At metabolic steady state, however, FA oxidation must match FA intake plus synthesis; moreover, 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 diurnal, 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 ± 19 vs 97 ± 14 mg/d, P< O.001) despite reduced energy intake from fat. This increase in FA oxidation was balanced by a 3-fold increase in FA synthesis compared to AL. Expression of fatty acid synthase and acetyl-CoA carboxylase mRNA were increased in adipose and in liver in a time-dependent manner. 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 oxidative damage and disease risk.

fat oxidation; fat synthesis; lipogenesis; palmitoleate; heavy water