Aims/hypothesis Calorie restriction is an essential component in the treatment of obesity and associated diseases. Longchain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice. Methods Male mice (C57BL/6J) were habituated to a cornoil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF+F), ad libitum; (3) cHF with calorie restriction (CR; cHF+CR); and (4) cHF+F+CR. Mice fed a chow diet were also studied. Results We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ 12,15 -prostaglandin J 2 and protectin D1. Conclusions/interpretation White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.

CDCA could reverse obesity in cHF-fed mice, mainly in response to the reduction in food intake, an effect probably occuring but neglected in previous studies using cholic acid. Nevertheless, CDCA-dependent and food intake-independent induction of UCP1 in BAT (but not in WAT) could contribute to the reduction in adiposity and to the stabilization of the lean phenotype.

Our results indicate integrated involvement of (i) TAG/FA cycling and DNL in WAT, and (ii) hepatic very-low-density lipoprotein-TAG synthesis in the control of blood lipid levels and provision of FA fuels for thermogenesis in cold. They suggest that lipogenesis in WAT contributes to a lean phenotype.