OBJECTIVE: Resolution of low-grade inflammation of white adipose tissue (WAT) is one of the keys for amelioration of obesity-associated metabolic dysfunctions. We focused on the identification of adipokines, which could be involved at the early stages of resolution of WAT inflammation. METHODS AND PROCEDURE: Male C57BL/6J mice with obesity induced in response to a 22-week feeding corn oil-based high-fat (cHF) diet were divided into four groups and were fed with, for 2 weeks, control cHF diet or cHF-based diets supplemented with: (i) concentrate of n-3 long-chain polyunsaturated fatty acids, mainly eicosapentaenoic and docosahexaenoic acids (cHF+F); (ii) thiazolidinedione drug rosiglitazone (cHF+TZD); and (iii) both compounds (cHF+F+TZD). RESULTS: The short-term combined intervention exerted additive effect in the amelioration of WAT inflammation in obese mice, namely in the epididymal fat, even in the absence of any changes in either adipocyte volume or fat mass. The combined intervention elicited hypolipidaemic effect and induced adiponectin, whereas the responses to single interventions (cHF+F, cHF+TZD) were less pronounced. In addition, analysis in WAT lysates using protein arrays revealed that the levels of a small set of adipose tissue-related proteins, namely macrophage inflammatory protein 1γ, endoglin, vascular cell adhesion molecule 1 and interleukin 1 receptor antagonist, changed in response to the anti-inflammatory interventions and were strongly reduced in the cHF+F+TZD mice. These results were verified using both the analysis of gene expression and enzyme-linked immunosorbent analysis in WAT lysates. In contrast with adiponectin, which showed changing plasma levels in response to dietary interventions, the levels of the above proteins were affected only in WAT. CONCLUSIONS: We identified several adipose tissue-related proteins, which are locally involved in resolution of low-grade inflammation and remodelling of WAT.

• MeSH
• Adipokines metabolism   MeSH
• Adipose Tissue, White metabolism   pathology   MeSH
• Diet, High-Fat MeSH
• Dietary Fats MeSH
• Enzyme-Linked Immunosorbent Assay MeSH
• Energy Metabolism MeSH
• Immunohistochemistry MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Docosahexaenoic Acids pharmacology   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Obese MeSH
• Mice MeSH
• Obesity immunology   pathology   MeSH
• Fatty Acids, Omega-3 pharmacology   MeSH
• Rosiglitazone MeSH
• Thiazolidinediones pharmacology   MeSH
• Adipocytes metabolism   MeSH
• Inflammation pathology   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
• Adipokines MeSH
• Dietary Fats MeSH
• Docosahexaenoic Acids MeSH
• Fatty Acids, Omega-3 MeSH
• Rosiglitazone MeSH
• Thiazolidinediones 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

In vitro experiments suggest that stimulation of lipolysis by catecholamines in adipocytes depends on the energy status of these cells. We tested whether mitochondrial uncoupling proteins (UCPs) that control the efficiency of ATP production could affect lipolysis and noradrenaline signalling in white fat in vivo. The lipolytic effect of noradrenaline was lowered by ectopic UCP1 in white adipocytes of aP2-Ucp1 transgenic mice, overexpressing the UCP1 gene from the aP2 gene promoter, reflecting the magnitude of UCP1 expression, the impaired stimulation of cAMP levels by noradrenaline and the reduction of the ATP/ADP ratio in different fat depots. Thus only subcutaneous but not epididymal fat was affected. UCP1 also down-regulated the expression of hormone-sensitive lipase and lowered its activity, and altered the expression of trimeric G-proteins in adipocytes. The adipose tissue content of the stimulatory G-protein alpha subunit was increased while that of the inhibitory G-protein alpha subunits decreased in response to UCP1 expression. Our results support the idea that the energy status of cells, and the ATP/ADP ratio in particular, modulates the lipolytic effects of noradrenaline in adipose tissue in vivo. They also demonstrate changes at the G-protein level that tend to overcome the reduction of lipolysis when ATP level in adipocytes is low. Therefore, respiratory uncoupling may exert a broad effect on hormonal signalling in adipocytes.

• MeSH
• Adenosine Diphosphate metabolism   MeSH
• Adenosine Triphosphate metabolism   MeSH
• Cyclic AMP metabolism   MeSH
• DNA Primers MeSH
• Genotype MeSH
• Hepatocytes enzymology   MeSH
• Ion Channels MeSH
• Lipase genetics   MeSH
• Lipolysis * MeSH
• Membrane Proteins genetics   physiology   MeSH
• Mitochondrial Proteins MeSH
• Mice, Inbred C57BL MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Norepinephrine metabolism   MeSH
• GTP-Binding Proteins metabolism   MeSH
• Gene Expression Regulation, Enzymologic MeSH
• Base Sequence MeSH
• Carrier Proteins genetics   physiology   MeSH
• Adipose Tissue enzymology   metabolism   MeSH
• Uncoupling Protein 1 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
• Adenosine Diphosphate MeSH
• Adenosine Triphosphate MeSH
• Cyclic AMP MeSH
• DNA Primers MeSH
• Ion Channels MeSH
• Lipase MeSH
• Membrane Proteins MeSH
• Mitochondrial Proteins MeSH
• Norepinephrine MeSH
• GTP-Binding Proteins MeSH
• Carrier Proteins MeSH
• Ucp1 protein, mouse MeSH Browser
• Uncoupling Protein 1 MeSH