AIMS/HYPOTHESIS: Calorie restriction is an essential component in the treatment of obesity and associated diseases. Long-chain 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 corn-oil-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.

• MeSH
• Adipose Tissue, White drug effects   metabolism   MeSH
• Diet, High-Fat MeSH
• Dietary Fats pharmacology   MeSH
• Energy Metabolism drug effects   MeSH
• Immunohistochemistry MeSH
• Caloric Restriction * MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Docosahexaenoic Acids metabolism   MeSH
• Lipid Metabolism drug effects   MeSH
• Mice, Obese MeSH
• Mice MeSH
• Fatty Acids, Omega-3 pharmacology   MeSH
• Prostaglandin D2 analogs & derivatives   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 9-deoxy-delta-9-prostaglandin D2 MeSH Browser
• Dietary Fats MeSH
• Docosahexaenoic Acids MeSH
• Fatty Acids, Omega-3 MeSH
• Prostaglandin D2 MeSH
• protectin D1 MeSH Browser

AIMS/HYPOTHESIS: Intake of n-3 polyunsaturated fatty acids reduces adipose tissue mass, preferentially in the abdomen. The more pronounced effect of marine-derived eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on adiposity, compared with their precursor alpha-linolenic acid, may be mediated by changes in gene expression and metabolism in white fat. METHODS: The effects of EPA/DHA concentrate (6% EPA, 51% DHA) admixed to form two types of high-fat diet were studied in C57BL/6J mice. Oligonucleotide microarrays, cDNA PCR subtraction and quantitative real-time RT-PCR were used to characterise gene expression. Mitochondrial proteins were quantified using immunoblots. Fatty acid oxidation and synthesis were measured in adipose tissue fragments. RESULTS: Expression screens revealed upregulation of genes for mitochondrial proteins, predominantly in epididymal fat when EPA/DHA concentrate was admixed to a semisynthetic high-fat diet rich in alpha-linolenic acid. This was associated with a three-fold stimulation of the expression of genes encoding regulatory factors for mitochondrial biogenesis and oxidative metabolism (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [Ppargc1a, also known as Pgc1alpha] and nuclear respiratory factor-1 [Nrf1] respectively). Expression of genes for carnitine palmitoyltransferase 1A and fatty acid oxidation was increased in epididymal but not subcutaneous fat. In the former depot, lipogenesis was depressed. Similar changes in adipose gene expression were detected after replacement of as little as 15% of lipids in the composite high-fat diet with EPA/DHA concentrate, while the development of obesity was reduced. The expression of Ppargc1a and Nrf1 was also stimulated by n-3 polyunsaturated fatty acids in 3T3-L1 cells. CONCLUSIONS/INTERPRETATION: The anti-adipogenic effect of EPA/DHA may involve a metabolic switch in adipocytes that includes enhancement of beta-oxidation and upregulation of mitochondrial biogenesis.

• MeSH
• Epididymis drug effects   metabolism   MeSH
• NF-E2-Related Factor 1 drug effects   genetics   MeSH
• Carnitine O-Palmitoyltransferase drug effects   genetics   MeSH
• Cells, Cultured MeSH
• alpha-Linolenic Acid pharmacology   MeSH
• Eicosapentaenoic Acid pharmacology   MeSH
• Docosahexaenoic Acids pharmacology   MeSH
• Lipogenesis drug effects   MeSH
• Mitochondrial Proteins drug effects   metabolism   MeSH
• Mitochondria drug effects   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Fatty Acids, Unsaturated isolation & purification   metabolism   pharmacology   MeSH
• Obesity prevention & control   MeSH
• Oxidation-Reduction MeSH
• Subcutaneous Fat drug effects   metabolism   MeSH
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
• Gene Expression Regulation drug effects   MeSH
• Fish Oils chemistry   MeSH
• Trans-Activators drug effects   genetics   MeSH
• Transcription Factors MeSH
• Adipose Tissue drug effects   metabolism   MeSH
• Adipocytes drug effects   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• NF-E2-Related Factor 1 MeSH
• Carnitine O-Palmitoyltransferase MeSH
• alpha-Linolenic Acid MeSH
• Eicosapentaenoic Acid MeSH
• Docosahexaenoic Acids MeSH
• Mitochondrial Proteins MeSH
• Fatty Acids, Unsaturated MeSH
• Ppargc1a protein, mouse MeSH Browser
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
• Fish Oils MeSH
• Trans-Activators MeSH
• Transcription Factors MeSH