Metabolic dysfunction-associated steatotic liver disease (MASLD) occurs in subjects with obesity and metabolic syndrome. MASLD may progress from simple steatosis (i.e., hepatic steatosis) to steatohepatitis, characterized by inflammatory changes and liver cell damage, substantially increasing mortality. Lifestyle measures associated with weight loss and/or appropriate diet help reduce liver fat accumulation, thereby potentially limiting progression to steatohepatitis. As for diet, both total energy and macronutrient composition significantly influence the liver's fat content. For example, the type of dietary fatty acids can affect the metabolism of lipids and hence their tissue accumulation, with saturated fatty acids having a greater ability to promote fat storage in the liver than polyunsaturated ones. In particular, polyunsaturated fatty acids of n-3 series (omega-3), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have been intensively studied for their antisteatotic effects, both in preclinical animal models of obesity and hepatic steatosis and in overweight/obese patients. Their effects may depend not only on the dose and duration of administration of omega-3, or DHA/EPA ratio, but also on the lipid class used for their supplementation. This review summarizes the available evidence from recent comparative studies using omega-3 supplementation via different lipid classes. Albeit the evidence is mainly limited to preclinical studies, it suggests that phospholipids and possibly wax esters could provide greater efficacy against MASLD compared to traditional chemical forms of omega-3 supplementation (i.e., triacylglycerols, ethyl esters). This cannot be attributed solely to improved EPA and/or DHA bioavailability, but other mechanisms may be involved. Keywords: MASLD • Metabolic dysfunction-associated steatotic liver disease • NAFLD • Non-alcoholic fatty liver disease • n-3 polyunsaturated fatty acids.

• MeSH
• Liver * metabolism   drug effects   pathology   MeSH
• Humans MeSH
• Lipid Metabolism drug effects   MeSH
• Non-alcoholic Fatty Liver Disease metabolism   drug therapy   diet therapy   pathology   MeSH
• Obesity metabolism   drug therapy   diet therapy   pathology   MeSH
• Fatty Acids, Omega-3 * administration & dosage   metabolism   therapeutic use   MeSH
• Dietary Supplements * MeSH
• Fatty Liver metabolism   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Fatty Acids, Omega-3 * MeSH

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is associated with abnormalities of liver lipid metabolism. On the contrary, a diet enriched with n-3 polyunsaturated fatty acids (n-3-PUFAs) has been reported to ameliorate the progression of NAFLD. The aim of our study was to investigate the impact of dietary n-3-PUFA enrichment on the development of NAFLD and liver lipidome. Mice were fed for 6 weeks either a high-fat methionine choline-deficient diet (MCD) or standard chow with or without n-3-PUFAs. Liver histology, serum biochemistry, detailed plasma and liver lipidomic analyses, and genome-wide transcriptome analysis were performed. Mice fed an MCD developed histopathological changes characteristic of NAFLD, and these changes were ameliorated with n-3-PUFAs. Simultaneously, n-3-PUFAs decreased serum triacylglycerol and cholesterol concentrations as well as ALT and AST activities. N-3-PUFAs decreased serum concentrations of saturated and monounsaturated free fatty acids (FAs), while increasing serum concentrations of long-chain PUFAs. Furthermore, in the liver, the MCD significantly increased the hepatic triacylglycerol content, while the administration of n-3-PUFAs eliminated this effect. Administration of n-3-PUFAs led to significant beneficial differences in gene expression within biosynthetic pathways of cholesterol, FAs, and pro-inflammatory cytokines (IL-1 and TNF-α). To conclude, n-3-PUFA supplementation appears to represent a promising nutraceutical approach for the restoration of abnormalities in liver lipid metabolism and the prevention and treatment of NAFLD.

• Keywords
• lipidome, lipids, n-3 fatty acids, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis,
• MeSH
• Cholesterol metabolism   MeSH
• Choline metabolism   MeSH
• Diet, High-Fat adverse effects   MeSH
• Liver metabolism   MeSH
• Fatty Acids, Nonesterified metabolism   MeSH
• Methionine metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease * etiology   genetics   MeSH
• Fatty Acids, Unsaturated metabolism   MeSH
• Fatty Acids, Omega-3 * pharmacology   therapeutic use   metabolism   MeSH
• Racemethionine metabolism   pharmacology   MeSH
• Triglycerides metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholesterol MeSH
• Choline MeSH
• Fatty Acids, Nonesterified MeSH
• Methionine MeSH
• Fatty Acids, Unsaturated MeSH
• Fatty Acids, Omega-3 * MeSH
• Racemethionine MeSH
• Triglycerides MeSH

Preclinical evidence suggests that n-3 fatty acids EPA and DHA (Omega-3) supplemented as phospholipids (PLs) may be more effective than triacylglycerols (TAGs) in reducing hepatic steatosis. To further test the ability of Omega-3 PLs to alleviate liver steatosis, we used a model of exacerbated non-alcoholic fatty liver disease based on high-fat feeding at thermoneutral temperature. Male C57BL/6N mice were fed for 24 weeks a lard-based diet given either alone (LHF) or supplemented with Omega-3 (30 mg/g diet) as PLs (krill oil; ω3PL) or TAGs (Epax 3000TG concentrate; ω3TG), which had a similar total content of EPA and DHA and their ratio. Substantial levels of TAG accumulation (~250 mg/g) but relatively low inflammation/fibrosis levels were achieved in the livers of control LHF mice. Liver steatosis was reduced by >40% in the ω3PL but not ω3TG group, and plasma ALT levels were markedly reduced (by 68%) in ω3PL mice as well. Krill oil administration also improved hepatic insulin sensitivity, and its effects were associated with high plasma adiponectin levels (150% of LHF mice) along with superior bioavailability of EPA, increased content of alkaloids stachydrine and trigonelline, suppression of lipogenic gene expression, and decreased diacylglycerol levels in the liver. This study reveals that in addition to Omega-3 PLs, other constituents of krill oil, such as alkaloids, may contribute to its strong antisteatotic effects in the liver.

• Keywords
• C57BL/6N mice, NAFLD, high-fat diet, krill oil, obesity, omega-3, phospholipids, thermoneutral temperature,
• MeSH
• Housing, Animal MeSH
• Diet, High-Fat adverse effects   MeSH
• Euphausiacea MeSH
• Phospholipids pharmacology   MeSH
• Animal Nutritional Physiological Phenomena MeSH
• Insulin Resistance MeSH
• Liver metabolism   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Non-alcoholic Fatty Liver Disease etiology   therapy   MeSH
• Obesity etiology   therapy   MeSH
• Dietary Supplements * MeSH
• Fish Oils pharmacology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Phospholipids MeSH
• Fish Oils MeSH

Intestinal homeostasis is precisely regulated by a number of endogenous regulatory molecules but significantly influenced by dietary compounds. Malfunction of this system may result in chronic inflammation and cancer. Dietary essential n-3 polyunsaturated fatty acids (PUFAs) and short-chain fatty acid butyrate produced from fibre display anti-inflammatory and anticancer activities. Both compounds were shown to modulate the production and activities of TNF family cytokines. Cytokines from the TNF family (TNF- α, TRAIL, and FasL) have potent inflammatory activities and can also regulate apoptosis, which plays an important role in cancer development. The results of our own research showed enhancement of apoptosis in colon cancer cells by a combination of either docosahexaenoic acid (DHA) or butyrate with TNF family cytokines, especially by promotion of the mitochondrial apoptotic pathway and modulation of NF κ B activity. This review is focused mainly on the interaction of dietary PUFAs and butyrate with these cytokines during colon inflammation and cancer development. We summarised recent knowledge about the cellular and molecular mechanisms involved in such effects and outcomes for intestinal cell behaviour and pathologies. Finally, the possible application for the prevention and therapy of colon inflammation and cancer is also outlined.

• MeSH
• Apoptosis MeSH
• Butyrates metabolism   MeSH
• Cytokines metabolism   MeSH
• Diet MeSH
• Colon pathology   MeSH
• Docosahexaenoic Acids metabolism   MeSH
• Humans MeSH
• Mitochondria pathology   MeSH
• Mice MeSH
• Neoplasms metabolism   MeSH
• Fatty Acids, Unsaturated metabolism   MeSH
• NF-kappa B metabolism   MeSH
• Intestinal Mucosa metabolism   MeSH
• Tumor Necrosis Factors metabolism   MeSH
• Inflammation metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Butyrates MeSH
• Cytokines MeSH
• Docosahexaenoic Acids MeSH
• Fatty Acids, Unsaturated MeSH
• NF-kappa B MeSH
• Tumor Necrosis Factors MeSH

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

Insulin resistance, the key defect in type 2 diabetes (T2D), is associated with a low capacity to adapt fuel oxidation to fuel availability, i.e., metabolic inflexibility. This, in turn, contributes to a further damage of insulin signaling. Effectiveness of T2D treatment depends in large part on the improvement of insulin sensitivity and metabolic adaptability of the muscle, the main site of whole-body glucose utilization. We have shown previously in mice fed an obesogenic high-fat diet that a combined use of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and thiazolidinediones (TZDs), anti-diabetic drugs, preserved metabolic health and synergistically improved muscle insulin sensitivity. We investigated here whether n-3 LC-PUFA could elicit additive beneficial effects on metabolic flexibility when combined with a TZD drug rosiglitazone. Adult male C57BL/6N mice were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various interventions: cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids (cHF+F), cHF with 10 mg rosiglitazone/kg diet (cHF+ROSI), cHF+F+ROSI, or chow-fed. Indirect calorimetry demonstrated superior preservation of metabolic flexibility to carbohydrates in response to the combined intervention. Metabolomic and gene expression analyses in the muscle suggested distinct and complementary effects of the interventions, with n-3 LC-PUFA supporting complete oxidation of fatty acids in mitochondria and the combination with n-3 LC-PUFA and rosiglitazone augmenting insulin sensitivity by the modulation of branched-chain amino acid metabolism. These beneficial metabolic effects were associated with the activation of the switch between glycolytic and oxidative muscle fibers, especially in the cHF+F+ROSI mice. Our results further support the idea that the combined use of n-3 LC-PUFA and TZDs could improve the efficacy of the therapy of obese and diabetic patients.

• MeSH
• Diet, High-Fat adverse effects   MeSH
• Glycolysis drug effects   MeSH
• Muscle Fibers, Skeletal drug effects   metabolism   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Metabolomics MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity etiology   metabolism   MeSH
• Fatty Acids, Omega-3 pharmacology   MeSH
• Oxidation-Reduction drug effects   MeSH
• Gene Expression Regulation drug effects   MeSH
• Rosiglitazone MeSH
• Drug Synergism 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
• Fatty Acids, Omega-3 MeSH
• Rosiglitazone MeSH
• Thiazolidinediones 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

BACKGROUND: Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) of marine origin exert multiple beneficial effects on health. Our previous study in mice showed that reduction of adiposity by LC n-3 PUFA was associated with both, a shift in adipose tissue metabolism and a decrease in tissue cellularity. The aim of this study was to further characterize the effects of LC n-3 PUFA on fat cell proliferation and differentiation in obese mice. METHODS: A model of inducible and reversible lipoatrophy (aP2-Cre-ERT2 PPARγL2/L2 mice) was used, in which the death of mature adipocytes could be achieved by a selective ablation of peroxisome proliferator-activated receptor γ in response to i.p. injection of tamoxifen. Before the injection, obesity was induced in male mice by 8-week-feeding a corn oil-based high-fat diet (cHF) and, subsequently, mice were randomly assigned (day 0) to one of the following groups: (i) mice injected by corn-oil-vehicle only, i.e."control" mice, and fed cHF; (ii) mice injected by tamoxifen in corn oil, i.e. "mutant" mice, fed cHF; (iii) control mice fed cHF diet with15% of dietary lipids replaced by LC n-3 PUFA concentrate (cHF+F); and (iv) mutant mice fed cHF+F. Blood and tissue samples were collected at days 14 and 42. RESULTS: Mutant mice achieved a maximum weight loss within 10 days post-injection, followed by a compensatory body weight gain, which was significantly faster in the cHF as compared with the cHF+F mutant mice. Also in control mice, body weight gain was depressed in response to dietary LC n-3 PUFA. At day 42, body weights in all groups stabilized, with no significant differences in adipocyte size between the groups, although body weight and adiposity was lower in the cHF+F as compared with the cHF mice, with a stronger effect in the mutant than in control mice. Gene expression analysis documented depression of adipocyte maturation during the reconstitution of adipose tissue in the cHF+F mutant mice. CONCLUSION: Dietary LC n-3 PUFA could reduce both hypertrophy and hyperplasia of fat cells in vivo. Results are in agreement with the involvement of fat cell turnover in control of adiposity.

• MeSH
• Prostaglandin-Endoperoxide Synthases genetics   metabolism   MeSH
• Epididymis metabolism   pathology   MeSH
• Gene Expression MeSH
• Gene Knockout Techniques MeSH
• Corn Oil adverse effects   MeSH
• Mice, Transgenic MeSH
• Mice MeSH
• Obesity chemically induced   prevention & control   MeSH
• Fatty Acids, Omega-3 pharmacology   MeSH
• PPAR alpha genetics   metabolism   MeSH
• PPAR gamma genetics   MeSH
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
• Drug Evaluation, Preclinical MeSH
• Cell Proliferation drug effects   MeSH
• Proteins genetics   metabolism   MeSH
• Stearoyl-CoA Desaturase genetics   metabolism   MeSH
• Trans-Activators genetics   metabolism   MeSH
• Transcription Factors MeSH
• Adipocytes drug effects   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
• cyclooxygenase-3 MeSH Browser
• Prostaglandin-Endoperoxide Synthases MeSH
• fat-specific protein 27, mouse MeSH Browser
• Corn Oil MeSH
• Fatty Acids, Omega-3 MeSH
• PPAR alpha MeSH
• PPAR gamma MeSH
• Ppargc1a protein, mouse MeSH Browser
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MeSH
• Proteins MeSH
• Scd1 protein, mouse MeSH Browser
• Stearoyl-CoA Desaturase MeSH
• Trans-Activators MeSH
• Transcription Factors MeSH

OBJECTIVE: The induction of obesity, dyslipidemia, and insulin resistance by high-fat diet in rodents can be prevented by n-3 long-chain polyunsaturated fatty acids (LC-PUFAs). We tested a hypothesis whether AMP-activated protein kinase (AMPK) has a role in the beneficial effects of n-3 LC-PUFAs. RESEARCH DESIGN AND METHODS: Mice with a whole-body deletion of the α2 catalytic subunit of AMPK (AMPKα2(-/-)) and their wild-type littermates were fed on either a low-fat chow, or a corn oil-based high-fat diet (cHF), or a cHF diet with 15% lipids replaced by n-3 LC-PUFA concentrate (cHF+F). RESULTS: Feeding a cHF diet induced obesity, dyslipidemia, hepatic steatosis, and whole-body insulin resistance in mice of both genotypes. Although cHF+F feeding increased hepatic AMPKα2 activity, the body weight gain, dyslipidemia, and the accumulation of hepatic triglycerides were prevented by the cHF+F diet to a similar degree in both AMPKα2(-/-) and wild-type mice in ad libitum-fed state. However, preservation of hepatic insulin sensitivity by n-3 LC-PUFAs required functional AMPKα2 and correlated with the induction of adiponectin and reduction in liver diacylglycerol content. Under hyperinsulinemic-euglycemic conditions, AMPKα2 was essential for preserving low levels of both hepatic and plasma triglycerides, as well as plasma free fatty acids, in response to the n-3 LC-PUFA treatment. CONCLUSIONS: Our results show that n-3 LC-PUFAs prevent hepatic insulin resistance in an AMPKα2-dependent manner and support the role of adiponectin and hepatic diacylglycerols in the regulation of insulin sensitivity. AMPKα2 is also essential for hypolipidemic and antisteatotic effects of n-3 LC-PUFA under insulin-stimulated conditions.

• MeSH
• Cell Culture Techniques MeSH
• Diet, Fat-Restricted MeSH
• Dietary Fats pharmacology   MeSH
• Glucose Clamp Technique MeSH
• Hepatocytes cytology   physiology   MeSH
• Hyperinsulinism MeSH
• Insulin Resistance MeSH
• Liver drug effects   enzymology   physiology   MeSH
• Metabolic Syndrome prevention & control   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Fatty Acids, Unsaturated metabolism   pharmacology   MeSH
• Fatty Acids, Omega-3 metabolism   therapeutic use   MeSH
• Protein Subunits metabolism   MeSH
• AMP-Activated Protein Kinases deficiency   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Dietary Fats MeSH
• Fatty Acids, Unsaturated MeSH
• Fatty Acids, Omega-3 MeSH
• Protein Subunits MeSH
• Prkaa2 protein, mouse MeSH Browser
• AMP-Activated Protein Kinases MeSH