Fillets from marine fish species contain n-3 polyunsaturated fatty acids (PUFAs) in the form of phospholipids (PLs). To investigate the importance of PL-bound n-3 PUFAs in mediating the anti-obesogenic effect of lean seafood, we compared the anti-obesogenic properties of fillets from cod with fillets from pangasius, a fresh water fish with a very low content of PL-bound n-3 PUFAs. We prepared high-fat/high-protein diets using chicken, cod and pangasius as the protein sources, and fed male C57BL/6J mice these diets for 12 weeks. Mice fed the diet containing cod gained less adipose tissue mass and had smaller white adipocytes than mice fed the chicken-containing diet, whereas mice fed the pangasius-containing diet were in between mice fed the chicken-containing diet and mice fed the cod-containing diet. Of note, mice fed the pangasius-containing diet exhibited reduced glucose tolerance compared to mice fed the cod-containing diet. Although the sum of marine n-3 PUFAs comprised less than 2% of the total fatty acids in the cod-containing diet, this was sufficient to significantly increase the levels of eicosapentaenoic acid (EPA) and docosahexaenoic acids (DHA) in mouse tissues and enhance production of n-3 PUFA-derived lipid mediators as compared with mice fed pangasius or chicken.

• Keywords
• DHA, EPA, endocannabinoids, marine protein source, n-3 PUFA, nutrition, obesity and mice, phospholipids, seafood,
• MeSH
• Diet, High-Protein methods   MeSH
• Diet, High-Fat methods   MeSH
• Poultry Products MeSH
• Gadus morhua * MeSH
• Eicosapentaenoic Acid metabolism   MeSH
• Docosahexaenoic Acids metabolism   MeSH
• Anti-Obesity Agents analysis   MeSH
• Fatty Acids analysis   MeSH
• Lipid Metabolism MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Fatty Acids, Omega-3 analysis   MeSH
• Seafood analysis   MeSH
• Catfishes * MeSH
• Adipose Tissue metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Eicosapentaenoic Acid MeSH
• Docosahexaenoic Acids MeSH
• Anti-Obesity Agents MeSH
• Fatty Acids MeSH
• Fatty Acids, Omega-3 MeSH

Obesity is associated with insulin resistance and impaired glucose tolerance, which represent characteristic features of the metabolic syndrome. Development of obesity is also linked to changes in fatty acid and amino acid metabolism observed in animal models of obesity as well as in humans. The aim of this study was to explore whether plasma metabolome, namely the levels of various acylcarnitines and amino acids, could serve as a biomarker of propensity to obesity and impaired glucose metabolism. Taking advantage of a high phenotypic variation in diet-induced obesity in C57BL/6J mice, 12-week-old male and female mice (n = 155) were fed a high-fat diet (lipids ~32 wt%) for a period of 10 weeks, while body weight gain (BWG) and changes in insulin sensitivity (ΔHOMA-IR) were assessed. Plasma samples were collected before (week 4) and after (week 22) high-fat feeding. Both univariate and multivariate statistical analyses were then used to examine the relationships between plasma metabolome and selected phenotypes including BWG and ΔHOMA-IR. Partial least squares-discrimination analysis was able to distinguish between animals selected either for their low or high BWG (or ΔHOMA-IR) in male but not female mice. Among the metabolites that differentiated male mice with low and high BWG, and which also belonged to the major discriminating metabolites when analyzed in plasma collected before and after high-fat feeding, were amino acids Tyr and Orn, as well as acylcarnitines C16-DC and C18:1-OH. In general, the separation of groups selected for their low or high ΔHOMA-IR was less evident and the outcomes of a corresponding multivariate analysis were much weaker than in case of BWG. Thus, our results document that plasma acylcarnitines and amino acids could serve as a gender-specific complex biomarker of propensity to obesity, however with a limited predictive value in case of the associated impairment of insulin sensitivity.

• MeSH
• Amino Acids blood   MeSH
• Analysis of Variance MeSH
• Biomarkers MeSH
• Diet, High-Fat adverse effects   MeSH
• Phenotype MeSH
• Glucose Tolerance Test MeSH
• Insulin Resistance MeSH
• Carnitine analogs & derivatives   blood   MeSH
• Blood Glucose MeSH
• Metabolome MeSH
• Metabolomics methods   MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Obesity blood   diagnosis   etiology   MeSH
• Glucose Intolerance MeSH
• Prognosis MeSH
• Cluster Analysis MeSH
• Propensity Score MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• acylcarnitine MeSH Browser
• Amino Acids MeSH
• Biomarkers MeSH
• Carnitine MeSH
• Blood Glucose MeSH

OBJECTIVE: Besides their role in lipid absorption, bile acids (BAs) can act as signalling molecules. Cholic acid was shown to counteract obesity and associated metabolic disorders in high-fat-diet (cHF)-fed mice while enhancing energy expenditure through induction of mitochondrial uncoupling protein 1 (UCP1) and activation of non-shivering thermogenesis in brown adipose tissue (BAT). In this study, the effects of another natural BA, chenodeoxycholic acid (CDCA), on dietary obesity, UCP1 in both interscapular BAT and in white adipose tissue (brite cells in WAT), were characterized in dietary-obese mice. RESEARCH DESIGN: To induce obesity and associated metabolic disorders, male 2-month-old C57BL/6J mice were fed cHF (35% lipid wt wt(-1), mainly corn oil) for 4 months. Mice were then fed either (i) for 8 weeks with cHF or with cHF with two different doses (0.5%, 1%; wt wt(-1)) of CDCA (8-week reversion); or (ii) for 3 weeks with cHF or with cHF with 1% CDCA, or pair-fed (PF) to match calorie intake of the CDCA mice fed ad libitum; mice on standard chow diet were also used (3-week reversion). RESULTS: In the 8-week reversion, the CDCA intervention resulted in a dose-dependent reduction of obesity, dyslipidaemia and glucose intolerance, which could be largely explained by a transient decrease in food intake. The 3-week reversion revealed mild CDCA-dependent and food intake-independent induction of UCP1-mediated thermogenesis in interscapular BAT, negligible increase of UCP1 in subcutaneous WAT and a shift from carbohydrate to lipid oxidation. CONCLUSIONS: 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.

• MeSH
• Adipose Tissue, White metabolism   MeSH
• Diet, High-Fat MeSH
• Energy Metabolism MeSH
• Adipose Tissue, Brown metabolism   MeSH
• Ion Channels metabolism   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Chenodeoxycholic Acid metabolism   MeSH
• Lipid Metabolism MeSH
• Mitochondrial Proteins metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Obese MeSH
• Mice MeSH
• Obesity metabolism   MeSH
• Oxidative Stress MeSH
• Glucose Intolerance metabolism   MeSH
• Signal Transduction MeSH
• Thermogenesis * MeSH
• Uncoupling Protein 1 MeSH
• Blotting, Western 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
• Ion Channels MeSH
• Chenodeoxycholic Acid MeSH
• Mitochondrial Proteins MeSH
• Ucp1 protein, mouse MeSH Browser
• Uncoupling Protein 1 MeSH

BACKGROUND: n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides. METHODOLOGY/PRINCIPAL FINDINGS: In a 'prevention study', C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ∼35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine. CONCLUSIONS/SIGNIFICANCE: Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT.

• MeSH
• Analysis of Variance MeSH
• Adipose Tissue, White metabolism   MeSH
• Biological Availability MeSH
• Diet, High-Fat * MeSH
• Endocannabinoids * MeSH
• Phospholipids metabolism   MeSH
• Immunohistochemistry MeSH
• Liver drug effects   metabolism   MeSH
• Muscle, Skeletal metabolism   MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Eicosapentaenoic Acid metabolism   MeSH
• Docosahexaenoic Acids metabolism   MeSH
• Metabolomics MeSH
• Microscopy MeSH
• Cannabinoid Receptor Modulators metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity diet therapy   prevention & control   MeSH
• Fatty Acids, Omega-3 administration & dosage   metabolism   pharmacology   MeSH
• Body Weight MeSH
• Triglycerides 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
• Comparative Study MeSH
• Names of Substances
• Endocannabinoids * MeSH
• Phospholipids MeSH
• Eicosapentaenoic Acid MeSH
• Docosahexaenoic Acids MeSH
• Cannabinoid Receptor Modulators MeSH
• Fatty Acids, Omega-3 MeSH
• Triglycerides MeSH

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: Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor gamma, which improve whole-body insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity. METHODS: Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). RESULTS: DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, low-grade adipose tissue inflammation, dyslipidaemia and insulin resistance, while inducing adiponectin, suppressing hepatic lipogenesis and decreasing muscle ceramide concentration. The improvement in glucose tolerance reflected a synergistic stimulatory effect of the combined treatment on muscle glycogen synthesis and its sensitivity to insulin. The combination treatment also reversed dietary obesity, dyslipidaemia and IGT. CONCLUSIONS/INTERPRETATION: DHA/EPA and rosiglitazone can be used as complementary therapies to counteract dyslipidaemia and insulin resistance. The combination treatment may reduce dose requirements and hence the incidence of adverse side effects of thiazolidinedione therapy.

• MeSH
• Dietary Fats pharmacology   MeSH
• Glycogen biosynthesis   MeSH
• Hypoglycemic Agents pharmacology   MeSH
• Insulin physiology   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Corn Oil pharmacology   MeSH
• Eicosapentaenoic Acid pharmacology   MeSH
• Docosahexaenoic Acids pharmacology   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Fatty Acids, Omega-3 pharmacology   MeSH
• Glucose Intolerance metabolism   MeSH
• Rosiglitazone MeSH
• Thiazolidinediones pharmacology   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
• Dietary Fats MeSH
• Glycogen MeSH
• Hypoglycemic Agents MeSH
• Insulin MeSH
• Corn Oil MeSH
• Eicosapentaenoic Acid MeSH
• Docosahexaenoic Acids MeSH
• Fatty Acids, Omega-3 MeSH
• Rosiglitazone MeSH
• Thiazolidinediones MeSH