Bruss MD, Khambatta CF, Ruby MA, Aggarwal I, Hellerstein MK. Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates. Am J Physiol Endocrinol Metab 298: E108-E116, 2010. First published November 3, 2009 zdoi:10.1152/ajpendo.00524.2009.-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. However, at metabolic steady state, FA oxidation must match FA intake plus synthesis; moreover, FA intake is low, not high, during CR. Therefore, it is 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 2 days of CR being started, a shift to a cyclic, diurnal pattern of whole body FA metabolism occurred, with an initial phase of elevated endogenous FA synthesis [respiratory exchange ratio (RER) Ͼ1.10, lasting 4 -6 h after food provision], followed by a prolonged phase of FA oxidation (RER ϭ 0.70, lasting 18 -20 h). CR mice oxidized four times as much fat per day as ad libitum (AL)-fed controls (367 Ϯ 19 vs. 97 Ϯ 14 mg/day, P Ͻ O.001) despite reduced energy intake from fat. This increase in FA oxidation was balanced by a threefold increase in adipose tissue FA synthesis compared with AL. Expression of FA synthase and acetyl-CoA carboxylase mRNA were increased in adipose and liver in a timedependent 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 synthesis; lipogenesis; palmitoleate; heavy water CALORIE RESTRICTION (CR) delays the development of chronic disease and prolongs lifespan in mice (1,17,27,34). These effects correlate with a rapid induction in the expression of certain genes that persist as long as animals remain on CR (10, 36) even after energy balance is restored. These observations suggest the presence of a chronic signal of reduced energy availability that persists after energy balance has been reestablished. However, the underlying metabolic signals and adaptations responsible are not fully understood.Mice on CR regimens have been reported to exhibit increased expression of genes for fatty acid (FA) oxidation and decreased expression of genes for FA synthesis compared with ad libitum (AL)-fed controls (6,7,30,38). Due to differential entry points into the electron transport chain, a metabolic shift from carbohydrate to FA oxidation may reduce the production of reactive oxygen species (ROS) (15). A shift to FA oxidation thereby represents a potential mechanism for reduced oxidative damage, which has been proposed as a potential explanation for the health benefits of CR (14,15,29,35). It has also be...