trans-10-cis-12-conjugated-linoleic-acid and Insulin-Resistance

Hyperproinsulinaemia reflects both beta cell dysfunction and insulin resistance in cross-sectional studies, but it is not known whether changes in proinsulin concentrations are related to insulin resistance over time. As trans10cis12 (t10c12)-conjugated linoleic acid (CLA) supplementation induces insulin resistance in obese men, we used this fatty acid to investigate the effects on plasma proinsulin, insulin, C-peptide and adiponectin concentrations, including their associations with change in insulin sensitivity.. We randomised (double-blind) 57 non-diabetic abdominally obese men to receive either 3.4 g t10c12CLA, CLA-isomer mixture or control oil for 12 weeks. Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), intact proinsulin, insulin, the proinsulin : insulin ratio, C-peptide, glucose and adiponectin were assessed before and after supplementation.. Supplementation with t10c12CLA increased proinsulin (p<0.01), the proinsulin : insulin ratio (p<0.05) and C-peptide concentrations (p<0.001) in comparison with control subjects. Adiponectin, however, did not change significantly. The change in proinsulin, but not the proinsulin : insulin ratio, was related to impaired insulin sensitivity (r= -0.58, p<0.0001), independently of changes in insulin, C-peptide, glucose, adiponectin and BMI. Conversely, the correlation between insulin sensitivity and specific insulin (r=-0.46, p<0.001) did not remain significant after adjustment for proinsulin. Induced hyperproinsulinaemia was also correlated to adiponectin concentrations ( r= -0.34, p<0.01).. In obese men, t10c12CLA induces hyperproinsulinaemia that is related to impaired insulin sensitivity, independently of changes in insulin concentrations. These results are of clinical interest, as hyperproinsulinaemia predicts diabetes and cardiovascular disease. The use of weight-loss supplements containing this fatty acid is worrying.

Topics: Abdomen; Adiponectin; Adipose Tissue; Analysis of Variance; Blood Glucose; C-Peptide; Dietary Supplements; Double-Blind Method; Drug Administration Schedule; Humans; Hyperinsulinism; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Linoleic Acids, Conjugated; Male; Obesity; Time Factors

Mixtures of the two major conjugated linoleic acid (CLA) isomers trans-10,cis-12-CLA and cis-9,trans-11-CLA are used as over the counter supplements for weight loss. Because of the reported adverse effects of CLA on insulin sensitivity in some mouse studies, we sought to compare the impact of dietary t10c12-CLA and c9t11-CLA on liver, adipose tissue, and systemic metabolism of adult lean mice. We fed 8 week-old C57Bl/6J male mice with low fat diets (10.5% Kcal from fat) containing 0.8% t10c12-CLA or c9t11-CLA for 9 or 38 days. Diets containing c9t11-CLA had minimal impact on the endpoints studied. However, 7 days after starting the t10c12-CLA diet, we observed a dramatic reduction in fat mass measured by NMR spectroscopy, which interestingly rebounded by 38 days. This rebound was apparently due to a massive accumulation of lipids in the liver, because adipose tissue depots were visually undetectable. Hepatic steatosis and the disappearance of adipose tissue after t10c12-CLA feeding was associated with elevated plasma insulin levels and insulin resistance, compared to mice fed a control diet or c9t11-CLA diet. Unexpectedly, despite being insulin resistant, mice fed t10c12-CLA had normal levels of blood glucose, without signs of impaired glucose clearance. Hepatic gene expression and fatty acid composition suggested enhanced hepatic de novo lipogenesis without an increase in expression of gluconeogenic genes. These data indicate that dietary t10c12-CLA may alter hepatic glucose and lipid metabolism indirectly, in response to the loss of adipose tissue in mice fed a low fat diet.

Topics: Adipose Tissue; Animals; Dyslipidemias; Fatty Acids; Gene Expression Regulation; Glucose; Glucose Intolerance; Insulin Resistance; Isomerism; Linoleic Acids, Conjugated; Lipid Metabolism; Lipodystrophy; Lipogenesis; Liver; Male; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease

Supplementation with a mixture of trans-10, cis-12 (t10,c12) and cis-9, trans-11 (c9,t11) isomers of conjugated linoleic acid (CLA), or t10,c12 CLA alone, reduces body weight and fat deposition in animals and some humans. However, these anti-obesity actions of t10,c12 CLA are routinely accompanied by increased markers of inflammation and insulin resistance. Thus, we examined the extent to which blocking c-Jun NH2-terminal kinase (JNK) signaling using the JNK inhibitor SP600125 attenuated markers of inflammation and insulin resistance in primary human adipocytes treated with t10,c12 CLA. SP600125 attenuated t10,c12 CLA-mediated phosphorylation of cJun and increased protein levels of activating transcription factor (ATF) 3, two downstream targets of JNK. SP600125 attenuated t10,c12 CLA-mediated induction of inflammatory genes, including interleukin (IL)-6, IL-8, IL-1β, ATF3, monocyte chemoattractant protein (MCP)-1, and cyclooxygenase-2. Consistent with these data, SP600125 prevented t10,c12 CLA-mediated secretion of IL-8, IL-6, and MCP-1. SP600125 prevented t10,c12 CLA suppression of lipogenic genes including peroxisome proliferator activated receptor gamma, liver X receptor, sterol regulatory element binding protein, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. Additionally, SP600125 blocked t10,c12 CLA-mediated induction of suppressor of cytokine synthesis-3 and suppression of adiponectin and insulin-dependent glucose transporter 4 mRNA levels. Collectively, these data suggest that JNK signaling plays an important role in t10,c12 CLA-mediated regulation of inflammatory and lipogenic gene expression in primary cultures of human adipocytes.

Topics: Activating Transcription Factor 3; Adipocytes; Adult; Anthracenes; Cells, Cultured; Female; Gene Expression Regulation; Humans; Inflammation; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Linoleic Acids, Conjugated; Lipogenesis; Middle Aged; Signal Transduction; Young Adult

Obesity is associated with a high risk of developing diabetes and cardiovascular disease. Therefore, management of body weight to prevent obesity remains as an important priority. The present investigation addresses the effects of conjugated linoleic acid (CLA) isomers on body weight and composition of body fat in female C57Bl/6J mice. To investigate the differential effects of individual CLA isomers and their mixture on changes in lean mass, fat mass, glucose and insulin, 6-month-old female C57BL/6J mice were fed with 10% corn oil (CO) as a dietary fat source and either supplemented with purified cis 9,trans 11 (c9t11) CLA (0.5%) or trans 10,cis 12 (t10c12) CLA (0.5%) and/or their mixture (50:50) for 6 months. As a result of 6 months' dietary intervention, both the t10c12-CLA and CLA mix showed increased lean mass and reduced fat mass compared to the CO and c9t11-CLA groups. Insulin resistance was, however, increased in t10c12-CLA and CLA mix-fed groups based on the results of homeostasis model assessment (HOMA), the revised quantitative insulin-sensitivity check index (R-QUICKI) and also with intravenous glucose tolerance test (IVGTT). In conclusion, long-term feeding of the major CLA isomers in 12-month-old C57Bl/6J mice revealed a contrasting effect on fat mass, glucose and insulin metabolism. The t10c12 isomer is found to reduce the fat mass and increase the lean mass but significantly contributed to increase insulin resistance and liver steatosis, whereas c9t11 isomer prevented the insulin resistance.

Topics: Aging; Animals; Biomarkers; Body Constitution; Corn Oil; Dietary Fats, Unsaturated; Fatty Liver; Female; Glucose Intolerance; Hypertriglyceridemia; Inflammation Mediators; Insulin Resistance; Isomerism; Linoleic Acids, Conjugated; Mice; Mice, Inbred C57BL; Obesity; Sarcopenia; Time Factors

The capacity of skeletal muscle to contribute to glucose homeostasis depends on muscular insulin sensitivity. The expression of glucose transporter (GLUT)-4 is increased during myoblast differentiation, a process essential in maintenance of adult muscle. Therefore, processes that affect muscle differentiation may influence insulin dependent glucose homeostasis. Conjugated linoleic acids, and in particular trans-10, cis-12 CLA (t10, c12-CLA), are potent inducers of NF-kB in cultured skeletal myotubes, and NF-kB activation inhibits muscle differentiation. The aims of this study were to evaluate whether CLAs inhibit myogenic differentiation and lower GLUT4 mRNA expression and to address the involvement of NF-kB activation in potential effects of CLA on these processes.. Incubation of C2C12 cells with t10, c12-CLA blocked the formation of myotubes, which was accompanied by reduced expression of the muscle specific genes creatine kinase, myogenin, myosin heavy chain perinatal and myosin heavy chain IIB, as well as decreased GLUT4 mRNA levels. However, genetic blockade of NF-kB was not sufficient to restore reduced myosin heavy chain protein expression following t10, c12-CLA treatment. Surprisingly, in contrast to myotubes, t10, c12-CLA was not able to activate NF-kB transcriptional activity in myoblasts.. In conclusion, t10, c12-CLA inhibits myogenic differentiation and GLUT4 expression, independently from NF-kB activation.

Topics: Animals; Cell Differentiation; Cell Line; Gene Expression Regulation; Glucose Transporter Type 4; Insulin Resistance; Linoleic Acids, Conjugated; Mice; Muscle Development; Muscle Fibers, Skeletal; Myoblasts; Myosin Heavy Chains; NF-kappa B; Rats

Insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) are found in 35 and 30 % of US adults, respectively. Trans-10, cis-12-conjugated linoleic acid (CLA) has been found to cause both these disorders in several animal models. We hypothesised that IR and NAFLD caused by CLA result from n-3 fatty acid deficiency. Pathogen-free C57BL/6N female mice (aged 8 weeks; n 10) were fed either a control diet or diets containing trans-10, cis-12-CLA (0.5 %) or CLA+flaxseed oil (FSO) (0.5 %+0.5 %) for 8 weeks. Weights of livers, concentration of circulating insulin, values of homeostatic model 1 (HOMA1) for IR and HOMA1 for beta cell function were higher by 160, 636, 985 and 968 % in the CLA group compared with those in the control group. FSO decreased fasting glucose by 20 % and liver weights by 37 % compared with those in the CLA group; it maintained circulating insulin, HOMA1-IR and HOMA1 for beta cell function at levels found in the control group. CLA supplementation decreased n-6 and n-3 wt% concentrations of liver lipids by 57 and 73 % and increased the n-6:n-3 ratio by 58 % compared with corresponding values in the control group. FSO increased n-6 and n-3 PUFA in liver lipids by 33 and 342 % and decreased the n-6:n-3 ratio by 70 % compared with corresponding values in the CLA group. The present results suggest that some adverse effects of CLA may be due to n-3 PUFA deficiency and that these can be corrected by a concomitant increase in the intake of alpha-linolenic acid, 18 : 3n-3.

Topics: Animal Nutritional Physiological Phenomena; Animals; Blood Glucose; Body Weight; Disease Models, Animal; Eating; Fatty Liver; Female; Insulin; Insulin Resistance; Linoleic Acids, Conjugated; Linseed Oil; Lipid Metabolism; Lipids; Liver; Mice; Mice, Inbred C57BL; Organ Size

While conjugated linoleic acid (CLA) has received a great deal of attention as a supplement that can favourably modify body composition, its potential impact on insulin sensitivity has not received equal attention. The aim of the present work was to analyse the effects of trans-10,cis-12 CLA isomer on insulin sensitivity in hamsters fed an atherogenic diet. Hamsters were divided into three groups: one group was fed a chow diet (control) and the other two a semipurified atherogenic diet supplemented with 0.5% linoleic acid (LA) or trans-10,cis-12 CLA, respectively. Serum glucose, FFAs, insulin, leptin and adiponectin were measured using commercial kits. HOMA-IR was calculated using the formula of Matthews et al. PPARgamma mRNA was assessed in epididymal adipose tissue by reverse transcription-polymerase chain reaction (RT-PCR). After 6 weeks, atherogenic feeding produced an increase in body fat accumulation as compared with control feeding. The addition of trans-10,cis-12 CLA to the atherogenic diet avoided this feature. Atherogenic feeding also led to significantly higher serum concentrations of glucose, insulin, FFAs, as well as greater HOMA-IR values. trans-10,cis-12 CLA did not prevent these effects. No significant differences were found among experimental groups in serum leptin and adiponectin concentrations, nor in PPARgamma expression. In summary, although the addition of trans-10,cis-12 CLA to an atherogenic diet reduces fat accumulation, it does not improve the impairment of insulin action associated with this feeding. The maintenance of insulin resistance in hamsters fed the atherogenic CLA-enriched diet is probably due to the high serum FFA concentration observed in these animals.

Topics: Adiponectin; Adipose Tissue; Adiposity; Animals; Blood Glucose; Cricetinae; Diet; Diet, Atherogenic; Dietary Fats, Unsaturated; Epididymis; Fatty Acids, Nonesterified; Insulin; Insulin Resistance; Leptin; Linoleic Acid; Linoleic Acids, Conjugated; Male; Mesocricetus; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Conjugated linoleic acids (CLA) affect atherogenesis, but mechanisms are not well understood. We explored how two isomers of CLA, cis9, trans11-CLA and trans10, cis12-CLA, affected lipid and glucose metabolism, as well as hepatic protein expression, in apolipoprotein E knockout mice. After 12 wk of intervention, plasma triglyceride, NEFA, and glucose concentrations were significantly higher in the trans10, cis12-CLA group, whereas plasma triglyceride, NEFA, glucose, and insulin concentrations were significantly lower in the cis9, trans11-CLA group, compared with control mice consuming linoleic acid. Proteomics identified significant up- or down-regulation of 113 liver cytosolic proteins by either CLA isomer. Principal component analysis revealed that the treatment effect of cis9, trans11-CLA was mainly explained by the up-regulation of different posttranslational forms of heat shock protein 70 kD. In contrast, the treatment effect of trans10, cis12-CLA was mainly explained by up-regulation of key enzymes in the gluconeogenic, beta-oxidation, and ketogenesic pathways. Correlation analysis again emphasized the divergent effects of both CLA isomers on different pathways, but also revealed a linkage between insulin resistance and increased levels of hepatic serotransferrin. Thus, our systems biology approach provided novel insights into the mechanisms by which individual CLA isomers differentially affect pathways related to atherogenesis, such as insulin resistance and inflammation.

Topics: Animal Feed; Animals; Apolipoproteins E; Atherosclerosis; Blood Glucose; Blotting, Western; Body Composition; Body Weight; Cytosol; Diet; Fatty Acids; Genetic Linkage; Glucose; HSP70 Heat-Shock Proteins; Inflammation; Insulin; Insulin Resistance; Linoleic Acid; Linoleic Acids, Conjugated; Liver; Male; Mice; Mice, Knockout; Oxygen; Perfusion; Principal Component Analysis; Proteomics; Systems Biology; Triglycerides