Dietary capsaicin attenuates metabolic dysregulation in genetically obese diabetic mice

Metabolic dysregulation (e.g., hyperglycemia, hyperinsulinemia, hyperlipidemia, etc.) is a hallmark of obesity-related diseases such as insulin resistance, type 2 diabetes, and fatty liver disease. In this study, we assessed whether dietary capsaicin attenuated the metabolic dysregulation in genetically obese diabetic KKAy mice, which have severe diabetic phenotypes. Male KKAy mice fed a high-fat diet for 2 weeks received a 0.015% capsaicin supplement for a further 3 weeks and were compared with nonsupplemented controls. Dietary capsaicin markedly decreased fasting glucose/insulin and triglyceride levels in the plasma and/or liver, as well as expression of inflammatory adipocytokine genes (e.g., monocyte chemoattractant protein-1 and interleukin-6) and macrophage infiltration. At the same time expression of the adiponectin gene/protein and its receptor, AdipoR2, increased in adipose tissue and/or plasma, accompanied by increased activation of hepatic AMP-activated protein kinase, a marker of fatty acid oxidation. These findings suggest that dietary capsaicin reduces metabolic dysregulation in obese/diabetic KKAy mice by enhancing expression of adiponectin and its receptor. Capsaicin may be useful as a dietary factor for reducing obesity-related metabolic dysregulation.     

Effect of conjugated linoleic acid isomers on insulin resistance and mRNA levels of genes regulating energy metabolism in high-fat-fed rats

OBJECTIVE: We investigated the effects of specific conjugated linoleic acid (CLA) isomers on glucose metabolism and insulin resistance and on mRNA levels of genes important in glucose and lipid metabolism. METHODS: Sprague-Dawley rats were fed for 8 wk on a high-fat diet (45% kcal from fat) or one of three CLA-supplemented diets (1% CLA) containing differing isomers of CLA, including a mixture of CLAs (CLA mix), cis-9, trans-11-CLA (C9,T11-CLA), or trans-10, cis-12-CLA (T10,C12-CLA). RESULTS: Compared with the high-fat group, all the CLA groups had enhanced glucose tolerance. Insulin resistance index was significantly lower in the CLA-treated groups. No significant difference could be observed in the level of serum lipids between groups and in the activities of phosphoenolpyruvate carboxylase, glucose-6-phosphatase, and glucokinase. However, C9,T11-CLA and T10,C12-CLA significantly increased acyl coenzyme A oxidase mRNA in skeletal muscle. In addition, C9,T11-CLA increased hepatic acyl coenzyme A oxidase mRNA and skeletal muscle uncoupling protein-2 mRNA. The CLA mix showed intermediate effects on the levels of these genes. CONCLUSIONS: The addition of all types of CLA to Sprague-Dawley rats fed a high-fat diet can decrease insulin resistance. Possible mechanisms are increased fat oxidation and energy expenditure by increasing acyl coenzyme A oxidase and uncoupling protein-2 mRNA in the liver and/or skeletal muscle.     

Short-term feeding of conjugated linoleic acid does not induce hepatic steatosis in C57BL/6J mice

We investigated the effect of short-term feeding of conjugated linoleic acid (CLA) on adipose tissue weights, liver weight, hepatic lipid metabolism, and serum lipoprotein profiles in C57BL/6J mice. Mice were fed semi-synthetic diets containing either 6%, high-linoleic safflower oil (HL-SAF) or 4% HL-SAF+2% CLA for 1 wk. Short-term feeding of CLA showed an anti-obesity effect without inducing hepatomegaly in mice. In addition to the decline of hepatic triglyceride concentration, significant inhibition of A9 desaturation of fatty acid in the total liver lipids was found in CLA-fed mice. The CLA diet significantly increased the activities of peroxisomal beta-oxidation and decreased the activities of diacylglycerol acyltransferase, a triglyceride synthesis-related enzyme, in the liver. Moreover, serum lipoprotein profiles of CLA-fed mice showed preferable changes in the atherogenic indices. However, serum leptin and adiponectin were drastically decreased by CLA feeding, suggesting that prolonged administration of CLA would induce further decrease of serum adipocytokine levels, which may be a cause of lipodystrophy in mice. These results show that short-term feeding of CLA does not induce adverse effect in C57BL/6J mice.     

The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-gamma target genes, in dogs

Visceral adipose tissue and skeletal muscle have central roles in determining whole-body insulin sensitivity. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a potential mediator of insulin sensitivity. It can directly modulate the expression of genes that are involved in glucose and lipid metabolism, including GLUT4, lipoprotein lipase (LPL) and adipocytokines (leptin and adiponectin). In this study, we aimed to determine the effects of obesity-associated insulin resistance on mRNA expression of PPARgamma and its target genes. Dogs were studied when they were lean and at the end of an overfeeding period when they had reached a steady obese state. The use of a sensitive, real-time PCR assay allowed a relative quantification of mRNA expression for PPARgamma, LPL, GLUT4, leptin and adiponectin, in adipose tissue and skeletal muscle. In visceral adipose tissue and/or skeletal muscle, mRNA expression of PPARgamma, LPL and GLUT4 were at least 2-fold less in obese and insulin-resistant dogs compared with the same animals when they were lean and insulin-sensitive. The mRNA expression and plasma concentration of leptin was increased, whereas the plasma level and mRNA expression of adiponectin was decreased, by obesity. In adipose tissue, PPARgamma expression was correlated with leptin and adiponectin. These findings, in an original model of obesity induced by a prolonged period of overfeeding, showed that insulin resistance is associated with a decrease in PPARgamma mRNA expression that could dysregulate expression of several genes involved in glucose and lipid metabolism.     

Functional lipids and the prevention of the metabolic syndrome

The metabolic syndrome is increasingly prevalent in worldwide. The quality and quantity of dietary lipids could be important modulators associated with the cardiovascular morbidity and mortality. At present, functional lipids such as conjugated linoleic acid (CLA) and phospholipids have attracted considerable attention because of their beneficial biological effects in attenuating metabolic syndrome. Supplementation of CLA reduces abdominal white adipose tissues, serum triacylglycerol (TAG) level, and liver TAG level in obese Otsuka Long-Evans Tokushima Fatty OLETF rats. These effects were attributed to enhanced fatty acid beta-oxidation and suppressed fatty acid synthesis in the liver. In addition, CLA enhanced energy expenditure in these rats. Anti-hypertensive properties of CLA have also been demonstrated. In obese/diabetic OLETF and Zucker rats, feeding of CLA prevented the development of obesity-induced hypertension. This was associated with an altered production of physiologically active adipocytokines, such as adiponectin, leptin and angiotensinogen. In addition, CLA could alleviate the development of insulin resistance and fatty liver. Dietary phospholipids have physiological functions that are different to dietary TAG. We recently reported that phosphatidylcholine (PC) alleviated orotic acid-induced fatty-liver through the suppression of hepatic lipogenesis in rats, and omega 3-PC from salmon roe prevented the development of obesity-related diseases through the suppression of lipogenic gene expressions and the enhancement of lypolytic gene expressions in the liver of obese rats. However, reports which studying the nutritional functions of minor phospholipids, such as phosphatidylinositol (PI), are scarce. Our study indicated that dietary PI lowered lipids in the plasma and liver by suppressing hepatic TAG synthesis.     

共轭亚油酸对肥胖大鼠脂联素基因表达的影响

目的研究共轭亚油酸对饮食诱导肥胖大鼠脂联素基因表达的影响。方法选用雄性Wistar大鼠,随机分为对照组、高脂组、高脂+共轭亚油酸组(每100g饲料含共轭亚油酸分别为075g、150g、300g),每组动物10只,观察共轭亚油酸对肥胖大鼠胰岛素、血糖水平的影响,并应用RTPCR的方法检测脂联素、过氧化物酶体增殖物活性受体γ(PPARγ)的表达水平。结果高脂组大鼠血清胰岛素和血糖水平分别为(1111±273)μIU/ml,(509±066)mmol/L,075%、150%、300%剂量组胰岛素水平分别为(699±177)μIU/ml,(736±148)μIU/ml,(785±160)μIU/ml,血糖水平分别为(428±072)mmol/L,(418±055)mmol/L,(406±063)mmol/L,且共轭亚油酸可增加肥胖大鼠脂肪组织脂联素、PPARγmRNA的表达水平。结论共轭亚油酸可通过激活PPARγ上调脂联素基因的表达,改善肥胖大鼠的胰岛素抵抗。     

Combined Phyllostachys pubescens and Scutellaria baicalensis Prevent High-Fat Diet-Induced Obesity via Upregulating Thermogenesis and Energy Expenditure by UCP1 in Male C57BL/6J Mice

This study examined the anti-obesity effects of a Phyllostachys pubescens (leaf) and Scutellaria baicalensis root mixture (BS21), and its underlying mechanisms of action, in high-fat diet (HFD)-induced obese mice. Mice were fed a HFD with BS21 (100, 200, or 400 mg/kg) for 9 weeks. BS21 reduced body weight, white adipose tissue (WAT) and liver weights, liver lipid accumulation, and adipocyte size. Additionally, BS21 reduced serum concentrations of non-esterified fatty acid, triglyceride, glucose, lactate dehydrogenase, low-density lipoprotein cholesterol, total cholesterol, leptin, and insulin growth factor 1, but elevated the adiponectin concentrations. Furthermore, BS21 suppressed the mRNA levels of lipogenesis-related proteins, such as peroxisome proliferator–activated receptor (PPAR) γ, SREBP-1c, C/EBP-α, fatty acid synthase, and leptin, but increased the mRNA gene expression of lipolysis-related proteins, such as PPAR-α, uncoupling protein (UCP) 2, adiponectin, and CPT1b, in WAT. In addition, BS21 increased the cold-stimulated adaptive thermogenesis and UCP1 protein expression with AMPK activation in adipose tissue. Furthermore, BS21 increased the WAT and mRNA expression of energy metabolism-related proteins SIRT1, PGC-1α, and FNDC5/irisin in the quadriceps femoris muscle. These results suggest that BS21 exerts anti-obesity and antihyperlipidemic activities in HFD-induced obese mice by increasing the thermogenesis and energy expenditure, and regulating lipid metabolism. Therefore, BS21 could be useful for preventing and treating obesity and its related metabolic diseases.     

Interrelations between fat distribution, muscle lipid content, adipocytokines, and insulin resistance: effect of moderate weight loss in older women

BACKGROUND: Interrelations between fat distribution, muscle lipid infiltration, adipocytokines, insulin resistance, and moderate weight loss have not been investigated in obese older subjects. OBJECTIVE: The objective was to evaluate relations between fat distribution, muscle lipid content, adipocytokines, and insulin resistance in older women and the effects of moderate weight loss. DESIGN: In 35 healthy women aged 58-83 y, body mass index, waist circumference, sagittal abdominal diameter (SAD), and body composition measured by dual-energy X-ray absorptiometry were evaluated. A midthigh single computed tomography scan was performed to determine subcutaneous adipose tissue (AT), intermuscular AT (IAT), muscular tissue, and muscle lipid infiltration, evaluated as low-density lean tissue. Metabolic variables, insulin resistance measured by homeostasis model assessment, adiponectin, leptin, and high-sensitivity C-reactive protein were measured in all subjects and after weight loss in a subgroup of 15 obese women. RESULTS: Waist circumference and SAD were positively correlated with leptin and insulin resistance and negatively correlated with adiponectin. Adiponectin was associated negatively with insulin resistance and positively with HDL cholesterol, whereas leptin was positively associated with insulin resistance and triacylglycerols. Midthigh subcutaneous AT was associated with insulin resistance and leptin, whereas IAT was associated with triacylglycerols. Stepwise regression with insulin resistance as the dependent variable and body mass index, SAD, triacylglycerols, HDL cholesterol, adiponectin, leptin, high-sensitivity C-reactive protein, and midthigh subcutaneous AT as independent variables showed that SAD entered the regression first (R(2) = 0.492) followed by adiponectin (R(2) = 0.63). After moderate weight loss, midthigh subcutaneous AT, IAT, low-density lean tissue, leptin, and insulin resistance decreased significantly; no significant changes in adiponectin were observed. CONCLUSIONS: Fat distribution indexes and adiponectin are independently associated with insulin resistance. Even in older women, moderate weight loss improves body fat distribution, muscle lipid infiltration, and insulin resistance. Moderate weight loss results in a significant decrease in leptin but no changes in adiponectin.     

The conjugated linoleic acid (CLA) isomer,t10c12-CLA,is inversely associated with changes in body weight and serum leptin in subjects with type 2 diabetes mellitus

Isomers of conjugated linoleic acid (CLA) are found in beef, lamb and dairy products. Diets containing CLA reduce adipose mass in various depots of experimental animals. In addition, CLA delays the onset of diabetes in the ZDF rat model for obesity-linked type 2 diabetes mellitus. We hypothesize that there would be an inverse association of CLA with body weight and serum leptin in subjects with type 2 diabetes mellitus. In this double-blind study, subjects with type 2 diabetes mellitus were randomized into one of two groups receiving either a supplement containing mixed CLA isomers (CLA-mix; 8.0 g daily, 76% pure CLA; n = 12) or a supplement containing safflower oil (placebo; 8.0 g daily safflower oil, n = 9) for 8 wk. The isomers of CLA in the CLA-mix supplement were primarily c9t11-CLA ( approximately 37%) and t10c12-CLA ( approximately 39%) in free fatty acid form. Plasma levels of CLA were inversely associated with body weight (P < 0.05) and serum leptin levels (P < 0.05). When levels of plasma t10c12-CLA isomer were correlated with changes in body weight or serum leptin, t10c12-CLA, but not c9t11-CLA, was inversely associated with body weights (P < 0.05) and serum leptin (P < 0.02). These findings strongly suggest that the t10c12-CLA isomer may be the bioactive isomer of CLA to influence the body weight changes observed in subjects with type 2 diabetes. Future studies are needed to determine a causal relationship, if any, of t10c12-CLA or c9t11-CLA to modulate body weight and composition in subjects with type 2 diabetes. Furthermore, determining the ability of CLA isomers to influence glucose and lipid metabolism as well as markers of insulin sensitivity is imperative to understanding the role of CLA to aid in the management of type 2 diabetes and other related conditions of insulin resistance.     

Anti-diabetic effects including diabetic nephropathy of anti-osteoporotic trace minerals on diabetic mice

Objective

In our previous study to evaluate the effects of soluble silicon (Si) on bone metabolism, Si and coral sand (CS) as a natural Si-containing material suppressed peroxisome proliferator-activated receptor γ (PPARγ), which regulates both glucose and bone metabolism and increases adipogenesis at the expense of osteogenesis, leading to bone loss. In this study, we investigated the anti-diabetic effects of bone-seeking elements, Si and stable strontium (Sr), and CS as a natural material containing these elements using obese diabetic KKAy mice.

Methods

Weanling male mice were fed diets containing 1% Ca supplemented with CaCO₃ as the control and CS, and diets supplemented with 50 ppm Si or 750 ppm Sr to control diet for 56 d. The mRNA expressions related to energy expenditure in the pancreas and kidney were quantified by real-time polymerase chain reaction.

Results

At the end of feeding, plasma glucose, insulin, leptin, and adiponectin levels decreased significantly in three test groups, while pancreatic PPARγ and adiponectin mRNA expression levels increased significantly toward the normal level, improving the glucose sensitivity of β-cells and inducing a significant decrease in insulin expression. The renal PPARγ, PPARα, and adiponectin expression levels, histologic indices of diabetic glomerulopathy, and plasma indices of renal function were also improved significantly in the test groups.

Conclusion

Taken together, anti-osteoporotic trace minerals, Si and Sr, and CS containing them showed novel anti-diabetic effects of lowering blood glucose level, improving the tolerance to insulin, leptin, and adiponectin, and reducing the risk of glomerulopathy through modulation of related gene expression in the pancreas and kidney.     

Specific preservation of biosynthetic responses to insulin in adipose tissue may contribute to hyperleptinemia in insulin-resistant obese mice

Obesity is characterized by whole-body insulin resistance, yet the expression of many insulin-stimulated genes, including leptin, is elevated in obesity. These observations suggest that insulin resistance may depend on tissue type and gene. To address this hypothesis, we examined the regulation of immediate-early gene expression in liver and adipose tissue after injection of insulin and glucose, in lean insulin-sensitive, and in A(y)/a obese insulin-sensitive and obese insulin-resistant mice. Expression of hepatic jun-B mRNA was robustly increased after insulin injection in lean insulin-sensitive a/a mice and insulin-sensitive A(y)/a mice. In contrast, induction of hepatic jun-B and c-fos gene expression by insulin was markedly attenuated in obese insulin-resistant mice. Surprisingly, induction of adipose jun-B and c-fos gene expression by insulin was markedly enhanced in obese insulin-resistant mice. Furthermore, the expressions of jun-B and leptin were also enhanced in insulin-resistant mice after injection of glucose. Leptin mRNA was positively correlated with blood glucose levels and jun-B mRNA in lean but not insulin-resistant mice. Multiple regression analysis indicated that the correlation between leptin mRNA and jun-B mRNA was significant even after removing the effect of blood glucose, but the correlation between leptin mRNA and glucose was no longer significant after removing the effect of jun-B mRNA. These data suggest that some impairments in biosynthetic responses to insulin are manifest primarily in the liver, leading to hyperinsulinemia and stimulating the expression of some adipose insulin-stimulated genes, including leptin. These studies demonstrate the utility of immediate-early gene expression in the analysis of biosynthetic mechanisms of insulin resistance.     

Effects of trans-10, cis-12 conjugated linoleic acid on the expression of uncoupling proteins in hamsters fed an atherogenic diet

It is known that conjugated linoleic acid (CLA) feeding decreases body adiposity but the mechanisms involved are not clear. The aim of this study was to analyse whether alterations in uncoupling protein (UCP) expression in white and brown adipose tissues (WAT and BAT, respectively) and in skeletal muscle may be responsible for the effect of trans-10, cis-12 CLA on the size of body fat depots in hamsters. Animals were divided into three groups and fed an atherogenic diet with different amounts of trans-10, cis-12 CLA (0 control, 0.5, or 1 g/100 g diet) for 6 weeks. CLA feeding reduced adipose depot weights, but had no effect on body weight. Leptin mRNA expression decreased in both subcutaneous and perirenal WAT depots, in accordance with lower adiposity, whereas resistin mRNA expression was not changed. Animals fed CLA had lower UCP1 mRNA levels in BAT (both doses of CLA) and in perirenal WAT (the low dose), and lower UCP3 mRNA levels in subcutaneous WAT (the high dose). UCP2 mRNA expression in WAT was not significantly affected by CLA feeding. Animals fed the high dose of CLA showed increased UCP3 and carnitine palmitoyl transferase-I (CPT-I) mRNA expression levels in skeletal muscle. In summary, induction of UCP1 or UCP2 in WAT and BAT is not likely to be responsible for the fat-reduction action of CLA, but the increased expression of UCP3 in skeletal muscle, together with a higher expression of CPT-I, may explain the previously reported effects of dietary CLA in lowering adiposity and increasing fatty acid oxidation by skeletal muscle.     

CLA-enriched diet containing t10,c12-CLA alters bile acid homeostasis and increases the risk of cholelithiasis in mice

Mice fed a mixture of CLA containing t10,c12-CLA lose fat mass and develop hyperinsulinemia and hepatic steatosis due to an accumulation of TG and cholesterol. Because cholesterol is the precursor in bile acid (BA) synthesis, we investigated whether t10,c12-CLA alters BA metabolism. In Expt. 1, female C57Bl/6J mice were fed a standard diet for 28 d supplemented with a CLA mixture (1 g/100 g) or not (controls). In Expt. 2, the feeding period was reduced to 4, 6, and 10 d. In Expt. 3, mice were fed a diet supplemented with linoleic acid, c9,t11-CLA, or t10,c12-CLA (0.4 g/100 g) for 28 d. In Expt. 1, the BA pool size was greater in CLA-fed mice than in controls and the entero-hepatic circulation of BA was altered due to greater BA synthesis and ileal reclamation. This resulted from higher hepatic cholesterol 7α-hydroxylase (CYP7A1) and ileal apical sodium BA transporter expressions in CLA-fed mice. Furthermore, hepatic Na(+)/taurocholate co-transporting polypeptide (NTCP) (-52%) and bile salt export pump (BSEP) (-77%) protein levels were lower in CLA-fed mice than in controls, leading to a greater accumulation of BA in the plasma (+500%); also, the cholesterol saturation index and the concentration of hydrophobic BA in the bile were greater in CLA-fed mice, changes associated with the presence of cholesterol crystals. Expt. 2 suggests that CLA-mediated changes were caused by hyperinsulinemia, which occurred after 6 d of the CLA diet before NTCP and BSEP mRNA downregulation (10 d). Expt. 3 demonstrated that only t10,c12-CLA altered NTCP and BSEP mRNA levels. In conclusion, t10,c12-CLA alters BA homeostasis and increases the risk of cholelithiasis in mice.     

Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance

OBJECTIVE: To study the effect of weight loss in response to a lifestyle modification program on the circulating levels of adipose tissue derived cytokines (adipokines) in obese individuals with insulin resistance. RESEARCH METHODS AND PROCEDURES: Twenty-four insulin-resistant obese subjects with varying degrees of glucose tolerance completed a 6-month program consisting of combined hypocaloric diet and moderate physical activity. Adipokines [leptin, adiponectin, resistin, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6)] and highly sensitive C-reactive protein were measured before and after the intervention. Insulin sensitivity index was evaluated by the frequently sampled intravenous glucose tolerance test. RESULTS: Participants had a 6.9 +/- 0.1 kg average weight loss, with a significant improvement in sensitivity index and reduction in plasma leptin (27.8 +/- 3 vs. 23.6 +/- 3 ng/mL, p = 0.01) and IL-6 (2.75 +/- 1.51 vs. 2.3 +/- 0.91 pg/mL, p = 0.012). TNF-alpha levels tended to decrease (2.3 +/- 0.2 vs. 1.9 +/- 0.1 pg/mL, p = 0.059). Adiponectin increased significantly only among diabetic subjects. The reductions in leptin were correlated with the decreases in BMI (r = 0.464, p < 0.05) and with changes in highly sensitive C-reactive protein (r = 0.466, p < 0.05). DISCUSSION: Weight reduction in obese individuals with insulin resistance was associated with a significant decrease in leptin and IL-6 and a tendency toward a decrease in circulating TNF-alpha, whereas adiponectin was increased only in diabetic subjects. Further studies are needed to elucidate the relationship between changes of adipokines and the health benefits of weight loss.     

Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity

OBJECTIVE: To evaluate interactions among leptin, adiponectin, resistin, ghrelin, and proinflammatory cytokines [tumor necrosis factor receptors (TNFRs), interleukin-6 (IL-6)] in nonmorbid and morbid obesity. RESEARCH METHODS AND PROCEDURES: We measured these hormones by immunoenzyme or radiometric assays in 117 nonmorbid and 57 morbidly obese patients, and in a subgroup of 34 morbidly obese patients before and 6 months after gastric bypass surgery. Insulin resistance by homeostasis model assessment, lipid profile, and anthropometrical measurements were also performed in all patients. RESULTS: Average plasma lipids in morbidly obese patients were elevated. IL-6, leptin, adiponectin, and resistin were increased and ghrelin was decreased in morbidly obese compared with nonmorbidly obese subjects. After adjusting for age, gender, and BMI in nonmorbidly obese, adiponectin was positively associated with HDLc and gender and negatively with weight (beta = -0.38, p < 0.001). Leptin and resistin correlated positively with soluble tumor necrosis factor receptor (sTNFR) 1 (beta = 0.24, p = 0.01 and beta = 0.28, p = 0.007). In the morbidly obese patients, resistin and ghrelin were positively associated with sTNFR2 (beta = 0.39, p = 0.008 and beta = 0.39, p = 0.01). In the surgically treated morbidly obese group, body weight decreased significantly and was best predicted by resistin concentrations before surgery (beta = 0.45, p = 0.024). Plasma lipids, insulin resistance, leptin, sTNFR1, and IL-6 decreased and adiponectin and ghrelin increased significantly. Insulin resistance improved after weight loss and correlated with high adiponectin levels. DISCUSSION: TNFalpha receptors were involved in the regulatory endocrine system of body adiposity independently of leptin and resistin axis in nonmorbidly obese patients. Our results suggest coordinated roles of adiponectin, resistin, and ghrelin in the modulation of the obesity proinflammatory environment and that resistin levels before surgery treatment are predictive of the extent of weight loss after bypass surgery.     

Effects of three different conjugated linoleic acid preparations on insulin signalling, fat oxidation and mitochondrial function in rats fed a high-fat diet

To investigate the effects of three different conjugated linoleic acid (CLA) preparations containing different ratios of CLA isomers on insulin signalling, fatty acid oxidation and mitochondrial function, Sprague-Dawley rats were fed a high-fat diet either unsupplemented or supplemented with one of three CLA preparations at 1 % of the diet for 8 weeks. The first CLA preparation contained approximately 30 % cis-9, trans-11 (c9, t11)-CLA isomer and 40 % trans-10, cis-12 (t10, c12)-CLA isomer (CLA-mix). The other two preparations were an 80:20 mix (c9, t11-CLA-mix) or a 10:90 mix of two CLA isomers (t10, c12-CLA-mix). Insulin resistance was decreased in all three supplemented groups based on the results of homeostasis model assessment and the revised quantitative insulin-sensitivity check index. The phosphorylation of insulin receptor substrate-1 on serine decreased in the livers of all three supplemented groups, while subsequent Akt phosphorylation increased only in the t10, c12-CLA-mix group. Both the c9, t11-CLA-mix and the t10, c12-CLA-mix increased the expression of hepatic adiponectin receptors R1 and 2, which are thought to enhance insulin sensitivity and fat oxidation. The c9, t11-CLA-mix increased protein and mRNA levels of PPAR alpha, acyl-CoA oxidase and uncoupling protein, which are involved in fatty acid oxidation and energy dissipation. The c9, t11-CLA-mix enhanced mitochondrial function and protection against oxidative stress by increasing the activities of cytochrome c oxidase, manganese-superoxide dismutase, glutathione peroxidase, and glutathione reductase and the level of GSH. In conclusion, all three CLA preparations reduced insulin resistance. Among them, the c9, t11-CLA-mix was the most effective based on the parameters reflecting insulin resistance and fat oxidation, and mitochondrial antioxidative enzyme activity in the liver.     

Conjugated linoleic acid induces mast cell recruitment during mouse mammary gland stromal remodeling

Conjugated linoleic acid (CLA) is a dietary chemopreventive agent that induces apoptosis in the mammary adipose vascular endothelium and decreases mammary brown adipose tissue (BAT) and white adipose tissue (WAT). To determine onset and extent of stromal remodeling, we fed CD2F1/Cr mice diets supplemented with 1 or 2 g/100 g mixed CLA isomers for 1-7 wk. BAT loss, collagen deposition, and leukocyte recruitment occurred in the mouse mammary fat pad, coincident with an increase in parenchymal-associated mast cells in mice fed both levels of CLA. Feeding experiments with purified isomers (0.5 g/100 g diet) demonstrated that these changes were induced by trans-10, cis-12 CLA (10,12-CLA), but not by cis-9, trans-11 CLA (9,11-CLA). This stromal remodeling did not require tumor necrosis factor (TNF)-alpha, a major cytokine in mast cells, as TNF-alpha null mice demonstrated collagen deposition, increased leukocytes, and BAT loss in the mammary fat pad in response to 10,12-CLA. To test the hypothesis that mast cells recruited in response to 10,12-CLA were required for stromal remodeling, Steel mice (WBB6F1/J-kit(W)/kit(W-V)), which lack functional mast cells, were examined for their stromal response to 10,12-CLA. Both wild-type and Steel mice showed a significantly increased leukocytic adipose infiltrate, collagen deposition, and decreased adipocyte size, although BAT was maintained in Steel mice. These results demonstrate that 10,12-CLA induces an inflammatory and fibrotic phenotype in the mouse mammary gland stroma that is independent of TNF-alpha or mast cells and suggest caution in the use of 10,12-CLA for breast cancer chemoprevention.