Type 2 diabetes (T2D) as well as cardiovascular disease (CVD) represent major complications of obesity and associated metabolic disorders (metabolic syndrome). This review focuses on the effects of long-chain n-3 polyunsaturated fatty acids (omega-3) on insulin sensitivity and glucose homeostasis, which are improved by omega-3 in many animal models of metabolic syndrome, but remain frequently unaffected in humans. Here we focus on: (i) mechanistic aspects of omega-3 action, reflecting also our experiments in dietary obese mice; and (ii) recent studies analysing omega-3's effects in various categories of human subjects. Most animal experiments document beneficial effects of omega-3 on insulin sensitivity and glucose metabolism even under conditions of established obesity and insulin resistance. Besides positive results obtained in both cross-sectional and prospective cohort studies on healthy human populations, also some intervention studies in prediabetic subjects document amelioration of impaired glucose homeostasis by omega-3. However, the use of omega-3 to reduce a risk of new-onset diabetes in prediabetic subjects still remains to be further characterized. The results of a majority of clinical trials performed in T2D patients suggest that omega-3 have none or marginal effects on metabolic control, while effectively reducing hypertriglyceridemia in these patients. Despite most of the recent randomized clinical trials do not support the role of omega-3 in secondary prevention of CVD, this issue remains still controversial. Combined interventions using omega-3 and antidiabetic or hypolipidemic drugs should be further explored and considered for treatment of patients with T2D and other diseases.

• MeSH
• diabetes mellitus 2. typu farmakoterapie   metabolismus   MeSH
• homeostáza účinky léků   MeSH
• inzulin krev   MeSH
• inzulinová rezistence * MeSH
• krevní glukóza metabolismus   MeSH
• kyseliny mastné omega-3 aplikace a dávkování   farmakokinetika   MeSH
• lidé MeSH
• medicína založená na důkazech MeSH
• myši MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy 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. PMID:19277604[PubMed - indexed for MEDLINE] Publication Types, MeSH Terms, SubstancesPublication TypesResearch Support, Non-U.S. Gov'tMeSH TermsAnimalsCorn Oil/pharmacologyDietary Fats/pharmacology*Docosahexaenoic Acids/pharmacologyEicosapentaenoic Acid/pharmacologyFatty Acids, Omega-3/pharmacology*Glucose Intolerance/metabolismGlycogen/biosynthesis*Hypoglycemic Agents/pharmacologyInsulin/physiology*MaleMiceMice, Inbred C57BLMuscle, Skeletal/drug effectsMuscle, Skeletal/metabolism*Thiazolidinediones/pharmacology*SubstancesDietary FatsFatty Acids, Omega-3Hypoglycemic AgentsThiazolidinedionesInsulinrosiglitazoneEicosapentaenoic AcidDocosahexaenoic AcidsCorn OilGlycogen LinkOut - more resourcesFull Text SourcesSpringerEBSCOOhioLINK Electronic Journal CenterProQuest Information and LearningSwets Information ServicesMedicalDietary Fats - MedlinePlus Health InformationDiabetes Medicines - MedlinePlus Health Information • Supplemental Content Related citations Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet. [Diabetologia. 2006] Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet. Flachs P, Mohamed-Ali V, Horakova O, Rossmeisl M, Hosseinzadeh-Attar MJ, Hensler M, Ruzickova J, Kopecky J. Diabetologia. 2006 Feb; 49(2):394-7. Epub 2006 Jan 6.Prominent role of liver in elevated plasma palmitoleate levels in response to rosiglitazone in mice fed high-fat diet. [J Physiol Pharmacol. 2009] Prominent role of liver in elevated plasma palmitoleate levels in response to rosiglitazone in mice fed high-fat diet. Kuda O, Stankova B, Tvrzicka E, Hensler M, Jelenik T, Rossmeisl M, Flachs P, Kopecky J. J Physiol Pharmacol. 2009 Dec; 60(4):135-40. Prevention and reversal of obesity and glucose intolerance in mice by DHA derivatives. [Obesity (Silver Spring). 2009] Prevention and reversal of obesity and glucose intolerance in mice by DHA derivatives. Rossmeisl M, Jelenik T, Jilkova Z, Slamova K, Kus V, Hensler M, Medrikova D, Povysil C, Flachs P, Mohamed-Ali V, et al. Obesity (Silver Spring). 2009 May; 17(5):1023-31. Epub 2009 Jan 15.Review N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? [Reprod Nutr Dev. 2004] Review N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity? Delarue J, LeFoll C, Corporeau C, Lucas D. Reprod Nutr Dev. 2004 May-Jun; 44(3):289-99. Review Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones. [Biochimie. 2003] Review Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones. Smith SA. Biochimie. 2003 Dec; 85(12):1219-30. See reviews... See all... Cited by 2 PubMed Central articles Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. [J Obes. 2011] Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. Bjorndal B, Burri L, Staalesen V, Skorve J, Berge RK. J Obes. 2011; 2011:490650. Epub 2011 Feb 15.Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus? [Lipids Health Dis. 2011] Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus? Das UN. Lipids Health Dis. 2011 Jan 24; 10:19. Epub 2011 Jan 24.All links from this record Related Citations Calculated set of PubMed citations closely related to the selected article(s) retrieved using a word weight algorithm. Related articles are displayed in ranked order from most to least relevant, with the “linked from” citation displayed first.Compound (MeSH Keyword) PubChem chemical compound records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.Substance (MeSH Keyword) PubChem chemical substance (submitted) records that are classified under the same Medical Subject Headings (MeSH) controlled vocabulary as the current articles.Cited in PMC Full-text articles in the PubMed Central Database that cite the current articles.

• MeSH
• dietní tuky farmakologie   MeSH
• glykogen biosyntéza   MeSH
• hypoglykemika farmakologie   MeSH
• inzulin fyziologie   MeSH
• kosterní svaly metabolismus   účinky léků   MeSH
• kukuřičný olej farmakologie   MeSH
• kyselina eikosapentaenová farmakologie   MeSH
• kyseliny dokosahexaenové farmakologie   MeSH
• kyseliny mastné omega-3 farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• porucha glukózové tolerance metabolismus   MeSH
• thiazolidindiony farmakologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

Combining pharmacological treatments and life style interventions is necessary for effective therapy of major diseases associated with obesity, which are clustered in the metabolic syndrome. Acting via multiple mechanisms, combination treatments may reduce dose requirements and, therefore, lower the risk of adverse side effects, which are usually associated with long-term pharmacological interventions. Our previous study in mice fed high-fat diet indicated additivity in preservation of insulin sensitivity and in amelioration of major metabolic syndrome phenotypes by the combination treatment using n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and rosiglitazone, i.e. an anti-diabetic drug of the thiazolidinedione (TZD) family. We investigated here whether pioglitazone, a TZD-drug in clinical use, could elicit the additive beneficial effects when combined with n-3 LC-PUFA. Adult male mice (C57BL/6N) were fed an obesogenic corn oil-based high-fat diet (cHF) for 8 weeks, or randomly assigned to various dietary treatments (i) cHF+F, cHF with n-3 LC-PUFA concentrate replacing 15% of dietary lipids; (ii) cHF+ROSI, cHF with 10 mg rosiglitazone/kg diet; (iii) cHF+F+ROSI; (iv) cHF+PIO, cHF with 50 mg pioglitazone/kg diet; and (v) cHF+F+PIO, or chow-fed. Plasma concentrations of 163 metabolites were evaluated using a targeted metabolomics approach. Both TZDs preserved glucose homeostasis and normal plasma lipid levels while inducing adiponectin, with pioglitazone showing better effectiveness. The beneficial effects of TZDs were further augmented by the combination treatments. cHF+F+ROSI but not cHF+F+PIO counteracted development of obesity, in correlation with inducibility of fatty acid β-oxidation, as revealed by the metabolomic analysis. By contrast, only cHF+F+PIO eliminated hepatic steatosis and this treatment also reversed insulin resistance in dietary obese mice. Our results reveal differential effects of rosiglitazone and pioglitazone, unmasked in the combination treatment with n-3 LC-PUFA, and support the notion that n-3 LC-PUFA could be used as add-on treatment to TZDs in order to improve diabetic patient's therapy.

• MeSH
• dietní tuky aplikace a dávkování   MeSH
• homeostáza MeSH
• hypoglykemika aplikace a dávkování   MeSH
• krevní glukóza analýza   MeSH
• kyseliny mastné omega-3 aplikace a dávkování   MeSH
• lipidy krev   MeSH
• metabolomika MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• obezita prevence a kontrola   MeSH
• thiazolidindiony aplikace a dávkování   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

This review provides evidence for the importance of white and brown adipose tissue (i.e. WAT and BAT) function for the maintenance of healthy metabolic phenotype and its preservation in response to omega-3 polyunsaturated fatty acids (omega-3 PUFA), namely in the context of diseased states linked to aberrant accumulation of body fat, systemic low-grade inflammation, dyslipidemia and insulin resistance. More specifically, the review deals with (i) the concept of immunometabolism, i.e. how adipose-resident immune cells and adipocytes affect each other and define the immune-metabolic interface; and (ii) the characteristic features of "healthy adipocytes" in WAT, which are relatively small fat cells endowed with a high capacity for mitochondrial oxidative phosphorylation, triacylglycerol/fatty acid (TAG/FA) cycling and de novo lipogenesis (DNL). The intrinsic metabolic features of WAT and their flexible regulations, reflecting the presence of "healthy adipocytes", provide beneficial local and systemic effects, including (i) protection against in situ endoplasmic reticulum stress and related inflammatory response during activation of adipocyte lipolysis; (ii) prevention of ectopic fat accumulation and dyslipidemia caused by increased hepatic VLDL synthesis, as well as prevention of lipotoxic damage of insulin signaling in extra-adipose tissues; and also (iii) increased synthesis of anti-inflammatory and insulin-sensitizing lipid mediators with pro-resolving properties, including the branched fatty acid esters of hydroxy fatty acids (FAHFAs), also depending on the activity of DNL in WAT. The "healthy adipocytes" phenotype can be induced in WAT of obese mice in response to various stimuli including dietary omega-3 PUFA, especially when combined with moderate calorie restriction, and possibly also with other life style (e.g. physical activity) or pharmacological (e.g. thiazolidinediones) interventions. While omega-3 PUFA could exert beneficial systemic effects by improving immunometabolism of WAT without a concomitant induction of BAT, it is currently not clear whether the metabolic effects of the combined intervention using omega-3 PUFA and calorie restriction or thiazolidinediones depend also on the activation of BAT function and/or the induction of brite/beige adipocytes in WAT. It remains to be established why omega-3 PUFA intervention in type 2 diabetic subjects does not improve insulin sensitivity and glucose homeostasis despite inducing various anti-inflammatory mediators in WAT, including the recently discovered docosahexaenoyl esters of hydroxy linoleic acid, the lipokines from the FAHFA family, as well as several endocannabinoid-related anti-inflammatory lipids. To answer the question whether and to which extent omega-3 PUFA supplementation could promote the formation of "healthy adipocytes" in WAT of human subjects, namely in the obese insulin-resistant patients, represents a challenging task that is of great importance for the treatment of some serious non-communicable diseases.

• MeSH
• bílá tuková tkáň účinky léků   metabolismus   MeSH
• inzulinová rezistence genetika   MeSH
• kyseliny mastné omega-3 metabolismus   terapeutické užití   MeSH
• lidé MeSH
• lipolýza účinky léků   MeSH
• metabolismus lipidů účinky léků   genetika   MeSH
• obezita dietoterapie   genetika   metabolismus   MeSH
• tukové buňky účinky léků   metabolismus   MeSH
• zánět dietoterapie   genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Omega-3 polyunsatuarted fatty acids (PUFA) are associated with hypolipidemic and anti-inflammatory effects. However, omega-3 PUFA, usually administered as triacylglycerols or ethyl esters, could also compromise glucose metabolism, especially in obese type 2 diabetics. Phospholipids represent an alternative source of omega-3 PUFA, but their impact on glucose homeostasis is poorly explored. Male C57BL/6N mice were fed for 8 weeks a corn oil-based high-fat diet (cHF) alone or cHF-based diets containing eicosapentaenoic acid and docosahexaenoic acid (~3%; wt/wt), admixed either as a concentrate of re-esterified triacylglycerols (ω3TG) or Krill oil containing mainly phospholipids (ω3PL). Lean controls were fed a low-fat diet. Insulin sensitivity (hyperinsulinemic-euglycemic clamps), parameters of glucose homeostasis, adipose tissue function, and plasma levels of N-acylethanolamines, monoacylglycerols and fatty acids were determined. Feeding cHF induced obesity and worsened (~4.3-fold) insulin sensitivity as determined by clamp. Insulin sensitivity was almost preserved in ω3PL but not ω3TG mice. Compared with cHF mice, endogenous glucose production was reduced to 47%, whereas whole-body and muscle glycogen synthesis increased ~3-fold in ω3PL mice that showed improved adipose tissue function and elevated plasma adiponectin levels. Besides eicosapentaenoic and docosapentaenoic acids, principal component analysis of plasma fatty acids identified palmitoleic acid (C16:1n-7) as the most discriminating analyte whose levels were increased in ω3PL mice and correlated negatively with the degree of cHF-induced glucose intolerance. While palmitoleic acid from Krill oil may help improve glucose homeostasis, our findings provide a general rationale for using omega-3 PUFA-containing phospholipids as nutritional supplements with potent insulin-sensitizing effects.

• MeSH
• dieta s vysokým obsahem tuků MeSH
• fosfolipidy aplikace a dávkování   metabolismus   MeSH
• glukosa metabolismus   MeSH
• homeostáza * MeSH
• inzulinová rezistence MeSH
• kyseliny mastné mononenasycené krev   MeSH
• myši inbrední C57BL MeSH
• myši obézní MeSH
• myši MeSH
• oleje rostlin metabolismus   MeSH
• potravní doplňky MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of this study was to estimate the effect of carnitine supplementation on lipid disorders and peripheral tissue insulin sensitivity in a non-obese animal model of insulin resistance, the hereditary hypertriglyceridemic (HHTg) rat. Male HHTg rats were fed a standard diet, and half of them received daily doses of carnitine (500 mg·kg(-1) body weight) for 8 weeks. Rats of the original Wistar strain were used for comparison. HHTg rats exhibited increased urinary excretion of free carnitine and reduced carnitine content in the liver and blood. Carnitine supplementation compensated for this shortage and promoted urinary excretion of acetylcarnitine without any signs of (acyl)carnitine accumulation in skeletal muscle. Compared with their untreated littermates, carnitine-treated HHTg rats exhibited lower weight gain, reduced liver steatosis, lower fasting triglyceridemia, and greater reduction of serum free fatty acid content after glucose load. Carnitine treatment was associated with increased mitochondrial biogenesis and oxidative capacity for fatty acids, amelioration of oxidative stress, and restored substrate switching in the liver. In skeletal muscle (diaphragm), carnitine supplementation was associated with significantly higher palmitate oxidation and a more favorable complete to incomplete oxidation products ratio. Carnitine supplementation further enhanced insulin sensitivity ex vivo. No effects on whole-body glucose tolerance were observed. Our data suggest that some metabolic syndrome-related disorders, particularly fatty acid oxidation, steatosis, and oxidative stress in the liver, could be attenuated by carnitine supplementation. The effect of carnitine could be explained, at least partly, by enhanced substrate oxidation and increased fatty acid transport from tissues in the form of short-chain acylcarnitines.

• MeSH
• genetická predispozice k nemoci MeSH
• homeostáza MeSH
• hypertriglyceridemie genetika   metabolismus   MeSH
• inzulinová rezistence MeSH
• játra metabolismus   MeSH
• karnitin aplikace a dávkování   analogy a deriváty   krev   metabolismus   farmakologie   moč   MeSH
• kosterní svaly metabolismus   MeSH
• krysa rodu rattus MeSH
• ledviny účinky léků   metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• mitochondriální DNA genetika   MeSH
• oxidační stres účinky léků   MeSH
• potravní doplňky MeSH
• regulace genové exprese účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH