Contribution of individual adiponectin isoforms to lipolysis regulation remains unknown. We investigated the impact of full-length, trimeric and globular adiponectin isoforms on spontaneous lipolysis in subcutaneous abdominal (SCAAT) and visceral adipose tissues (VAT) of obese and non-obese subjects. Furthermore, we explored the role of AMPK (5'-AMP-activated protein kinase) in adiponectin-dependent lipolysis regulation and expression of adiponectin receptors type 1 and 2 (AdipoR1 and AdipoR2) in SCAAT and VAT. Primary adipocytes isolated from SCAAT and VAT of obese and non-obese women were incubated with 20 µg/ml of: A) full-length adiponectin (physiological mixture of all adiponectin isoforms), B) trimeric adiponectin isoform or C) globular adiponectin isoform. Glycerol released into media was used as a marker of lipolysis. While full-length adiponectin inhibited lipolysis by 22% in non-obese SCAAT, globular isoform inhibited lipolysis by 27% in obese SCAAT. No effect of either isoform was detected in non-obese VAT, however trimeric isoform inhibited lipolysis by 21% in obese VAT (all p<0.05). Trimeric isoform induced Thr172 p-AMPK in differentiated preadipocytes from a non-obese donor, while globular isoform induced Ser79 p-ACC by 32% (p<0.05) and Ser565 p-HSL by 52% (p = 0.08) in differentiated preadipocytes from an obese donor. AdipoR2 expression was 17% and 37% higher than AdipoR1 in SCAAT of obese and non-obese groups and by 23% higher in VAT of obese subjects (all p<0.05). In conclusion, the anti-lipolytic effect of adiponectin isoforms is modified with obesity: while full-length adiponectin exerts anti-lipolytic action in non-obese SCAAT, globular and trimeric isoforms show anti-lipolytic activity in obese SCAAT and VAT, respectively.

• MeSH
• Adiponectin blood   chemistry   metabolism   MeSH
• Aminoimidazole Carboxamide analogs & derivatives   pharmacology   MeSH
• Adult MeSH
• Gene Expression drug effects   MeSH
• Hypoglycemic Agents pharmacology   MeSH
• Cells, Cultured MeSH
• Real-Time Polymerase Chain Reaction MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipolysis drug effects   MeSH
• Protein Multimerization drug effects   MeSH
• Intra-Abdominal Fat cytology   MeSH
• Obesity pathology   MeSH
• Subcutaneous Fat cytology   MeSH
• Protein Isoforms blood   chemistry   metabolism   MeSH
• AMP-Activated Protein Kinases metabolism   MeSH
• Receptors, Adiponectin genetics   metabolism   MeSH
• Ribonucleotides pharmacology   MeSH
• Adipocytes cytology   drug effects   metabolism   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adiponectin MeSH
• ADIPOR1 protein, human MeSH Browser
• ADIPOR2 protein, human MeSH Browser
• AICA ribonucleotide MeSH Browser
• Aminoimidazole Carboxamide MeSH
• Hypoglycemic Agents MeSH
• Protein Isoforms MeSH
• AMP-Activated Protein Kinases MeSH
• Receptors, Adiponectin MeSH
• Ribonucleotides 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

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