Effects of torula and brewer's yeast diets in obese and lean mice

Obese C57BL/6J-OB mice (ob/ob) and their lean littermates (?/+) were fed either torula yeast-based diet (TY) or brewer's yeast-based diet (BY) for a 23-d experimental period. Obese mice fed the BY diet had significantly lower liver weights than did mice fed the TY diet. Likewise, plasma glucose and insulin were significantly lower in obese mice fed the brewer's yeast diet (BY) than the torula yeast diet (TY). Liver weight and plasma glucose and insulin of lean mice were not significantly affected by diet during the experimental period. Despite the low Cr content of both TY and BY diets, bone Cr of the TY and BY groups was significantly higher than concentrations previously reported for the groups fed casein-based diets. The obese mouse may be particularly sensitive to Cr, making it a valuable model for elucidating effects of other dietary components on chromium status.     

Chromium alleviates glucose intolerance, insulin resistance, and hepatic ER stress in obese mice

Objective: Chromium has gained popularity as a nutritional supplement for diabetic patients. This study evaluated the effect of chronic administration of a chromium complex of d ‐phenylalanine (Cr(d ‐phe)₃) on glucose and insulin tolerance in obese mice. The study tested the hypothesis that Cr(d ‐phe)₃ suppresses endoplasmic reticulum (ER) stress and insulin resistance in these animals. Methods and Procedures: C57BL lean and ob/ob obese mice were randomly divided to orally receive vehicle or Cr(d ‐phe)₃ (3.8 μg of elemental chromium/kg/day) for 6 months. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Protein levels of phosphorylated pancreatic ER kinase (PERK), α subunit of translation initiation factor 2 (eIF2α) and inositol‐requiring enzyme‐1 (IRE‐1), p‐c‐Jun, and insulin receptor substrate‐1 (IRS‐1) phosphoserine‐307 were assessed by western blotting. In vitro ER stress was induced by treating cultured muscle cells with thapsigargin in the presence or absence of Cr(d ‐phe)₃. Results: ob/ob mice showed poor glucose and insulin tolerance compared to the lean controls, which was attenuated by Cr(d ‐phe)₃. Markers of insulin resistance (phospho‐c‐Jun and IRS‐1 phosphoserine) and ER stress (p‐PERK, p‐IRE‐1, p‐eIF2α), which were elevated in ob/ob mice, were attenuated following Cr(d ‐phe)₃ treatment. Chromium treatment was also associated with a reduction in liver triglyceride levels and lipid accumulation. In cultured myotubes, Cr(d ‐phe)₃ attenuated ER stress induced by thapsigargin. Discussion: Oral Cr(d ‐phe)₃ treatment reduces glucose intolerance, insulin resistance, and hepatic ER stress in obese, insulin‐resistant mice.     

Multi-block PCA and multi-compartmental study of the metabolic responses to intake of hydrolysed versus intact casein in C57BL/6J mice by NMR-based metabolomics

Recently we showed that exchanging intact casein with extensively hydrolysed casein in Western diets prevented diet-induced obesity in obesity-prone C57BL/6J mice. To gain further insight into the underlying mechanisms for the metabolic alterations induced by intake of hydrolysed casein, we performed an exploratory investigation using proton NMR spectroscopy, multi-block PCA (MBPCA) and a multi-compartment model including analyses of plasma, urine, faeces and tissue samples from mice fed diets with intact or hydrolysed casein and 16 or 32 energy% protein. The MBPCA superscores showed a clear separation between samples from mice fed intact and hydrolysed casein diets, respectively. Block loadings revealed that fecal fat content was higher, and tissue and plasma lipid levels were lower in mice fed hydrolysed casein diets compared with mice fed intact casein. Amino acid metabolism was also altered by dietary protein form, and levels of branched-chain amino acids were higher in faeces and urine and lower in plasma and spleen in mice fed hydrolysed protein. Moreover, hepatic levels of the sulphur-containing metabolites taurine and glutathione were increased in mice fed hydrolysed casein, and hepatic glycogen amount was increased in mice fed hydrolysed casein. In contrast, the levels of glucose and its metabolite lactate were reduced in faeces, liver and plasma. Taken together, NMR-based metabolomic analyses indicated that pathways within lipid, amino acid and carbohydrate metabolism were altered by intake of hydrolysed casein, and that these alterations are likely to be underlying mechanisms for the observed prevention against diet-induced obesity associated with hydrolysed casein intake.     

Chromium (D-phenylalanine)3 improves obesity-induced cardiac contractile defect in ob/ob mice

Objective: Low‐molecular weight chromium compounds, such as chromium picolinate [Cr(pic)₃], improve insulin sensitivity, although toxicity is a concern. We synthesized a novel chromium complex, chromium (d ‐phenylalanine)₃ [Cr(d ‐phe)₃], in an attempt to improve insulin sensitivity with reduced toxicity. The aim of this study was to compare the two chromium compounds on cardiac contractile function in ob/ob obese mice. Research Methods and Procedures: C57BL lean and ob/ob obese mice were randomly divided into three groups: H₂O, Cr(d ‐phe)₃, or Cr(pic)₃ (45 µg/kg per day orally for 6 months). Results: The glucose tolerance test displayed improved glucose clearance by Cr(d ‐phe)₃ but not Cr(pic)₃. Myocytes from ob/ob mice exhibited depressed peak shortening (PS) and maximal velocity of shortening/relengthening (±dL/dt), prolonged time‐to‐PS and time‐to‐90% relengthening (TR90), reduced electrically stimulated rise in intracellular Ca²⁺ (Δfura‐2 fluorescence intensity), and slowed intracellular Ca²⁺ decay. Although a 3‐month Cr(d ‐phe)₃ treatment for a separate group of ob/ob and lean 2‐month‐old mice only rectified reduced ±dL/dt in ob/ob mice, all mechanical and intracellular Ca²⁺ abnormalities were significantly attenuated or ablated by 6 months of Cr(d ‐phe)₃ but not Cr(pic)₃ treatment (except TR90). Sarco(endo)plasmic reticulum Ca²⁺ ATPase activity and Na⁺‐Ca²⁺ exchanger expression were depressed in ob/ob mice, which were reversed by both Cr(d ‐phe)₃ and Cr(pic)₃, with a more pronounced effect from Cr(d ‐phe)₃. Cr(d ‐phe)₃ corrected reduced insulin‐stimulated glucose uptake and improved basal phosphorylation of Akt and insulin receptor, as well as insulin‐stimulated phosphorylation of Akt and insulin receptor in ob/ob myocytes. Heart homogenates from ob/ob mice had enhanced oxidative stress and protein carbonyl formation compared with the lean group, which were attenuated by both Cr(d ‐phe)₃ and Cr(pic)₃. Discussion: Our data suggest that the new Cr(d ‐phe)₃ compound possesses better cardio‐protective and insulin‐sensitizing properties against obesity.     

Chromium (D-phenylalanine)3 alleviates high fat-induced insulin resistance and lipid abnormalities

High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (d-phenylalanine)₃ [Cr(d-Phe)₃] on glucose and insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(d-Phe)₃ (45 μg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body-glucose and -insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up-take in the gastrocnemius muscles, assessed as 2-[³H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-³²P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)₃. These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling.     

Comparison of Tissue Metal Concentrations in Zucker Lean, Zucker Obese, and Zucker Diabetic Fatty Rats and the Effects of Chromium Supplementation on Tissue Metal Concentrations

Diabetes results in several metabolic changes, including alterations in the transport, distribution, excretion, and accumulation of metals. While changes have been examined in several rat models of insulin resistance and diabetes, the metal ion concentrations in the tissues of Zucker lean, Zucker obese (an insulin resistance and early stage diabetes model), and Zucker diabetic fatty (ZDF, a type 2 diabetes model) have not previously been examined in detail. The concentration of Cu, Zn, Fe, Mg, and Ca were examined in the liver, kidney, heart and spleen, and Cr concentration in the liver and kidney of these rats were examined. Zucker obese rats have a reduction in the concentration of Cu, Zn, Fe, Mg in the liver compared to ZDF and/or lean Zucker rats, presumably as a result of the increased fat content of the liver of the obese rats. ZDF rats have increased concentrations of kidney Cu compared to the lean rats, while kidney Ca concentrations are increased in the Zucker obese rats. Spleen Fe concentrations are decreased in Zucker obese rats compared to the lean rats. No effects on metal concentrations in the heart were observed between the lean, obese, and ZDF rats, and no effects on Cr concentrations were identified. Cr(III) complexes have previously been shown to have beneficial effects on the signs of insulin resistance in Zucker obese and ZDF rats. The effects of daily gavage administration of chromium picolinate ([Cr(pic)₃]) (1 mg?Cr/kg body mass), CrCl₃ (1 mg?Cr/kg body mass), and Cr3 ([Cr₃O(propionate)₆(H₂O)₃]⁺) (33 μg and 1 mg?Cr/kg body mass) on metal concentrations in these tissues were examined. Treatment with CrCl₃ and Cr3, but not [Cr(pic)₃], at 1 mg?Cr/kg resulted in a statistically significant accumulation of Cr in the kidney of lean and obese but not ZDF rats but resulted in lowering the elevated levels of kidney Cu in ZDF rats, suggesting a beneficial effect on this symptom of type 2 diabetes.     

Effects of excess dietary iron and fat on glucose and lipid metabolism

PurposeDiets rich in fat and energy are associated with metabolic syndrome (MS). Increased body iron stores have been recognized as a feature of MS. High-fat diets (HFs), excess iron loading and MS are closely associated, but the mechanism linking them has not been clearly defined. We investigated the interaction between dietary fat and dietary Fe in the context of glucose and lipid metabolism in the body.MethodsC57BL6/J mice were divided into four groups and fed the modified AIN-93G low-fat diet (LF) and HF with adequate or excess Fe for 7 weeks. The Fe contents were increased by adding carbonyl iron (2% of diet weight) (LF+Fe and HF+Fe).ResultsHigh iron levels increased blood glucose levels but decreased high-density lipoprotein cholesterol levels. The HF group showed increases in plasma levels of glucose and insulin and insulin resistance. HF+Fe mice showed greater changes. Representative indices of iron status, such hepatic and plasma Fe levels, were not altered further by the HF. However, both the HF and excess iron loading changed the hepatic expression of hepcidin and ferroportin. The LF+Fe, HF and HF+Fe groups showed greater hepatic fat accumulation compared with the LF group. These changes were paralleled by alterations in the levels of enzymes related to hepatic gluconeogenesis and lipid synthesis, which could be due to increases in mitochondrial dysfunction and oxidative stress.ConclusionsHigh-fat diets and iron overload are associated with insulin resistance, modified hepatic lipid and iron metabolism and increased mitochondrial dysfunction and oxidative stress.     

Intake of Hydrolyzed Casein is Associated with Reduced Body Fat Accretion and Enhanced Phase II Metabolism in Obesity Prone C57BL/6J Mice

The amount and form of dietary casein have been shown to affect energy metabolism and lipid accumulation in mice, but the underlying mechanisms are not fully understood. We investigated 48 hrs urinary metabolome, hepatic lipid composition and gene expression in male C57BL/6J mice fed Western diets with 16 or 32 energy% protein in the form of extensively hydrolyzed or intact casein. LC-MS based metabolomics revealed a very strong impact of casein form on the urinary metabolome. Evaluation of the discriminatory metabolites using tandem mass spectrometry indicated that intake of extensively hydrolyzed casein modulated Phase II metabolism associated with an elevated urinary excretion of glucuronic acid- and sulphate conjugated molecules, whereas glycine conjugated molecules were more abundant in urine from mice fed the intact casein diets. Despite the differences in the urinary metabolome, we observed no differences in hepatic expression of genes involved in Phase II metabolism, but it was observed that expression of Abcc3 encoding ATP binding cassette c3 (transporter of glucuronic acid conjugates) was increased in livers of mice fed hydrolyzed casein. As glucuronic acid is derived from glucose and sulphate is derived from cysteine, our metabolomic data provided evidence for changes in carbohydrate and amino acid metabolism and we propose that this modulation of metabolism was associated with the reduced glucose and lipid levels observed in mice fed the extensively hydrolyzed casein diets.     

Obesity causes very low density lipoprotein clearance defects in low-density lipoprotein receptor-deficient mice

We have reported that obese leptin-deficient mice (ob/ob) lacking the low-density lipoprotein receptor (LDLR(-/-)) develop severe hyperlipidemia and spontaneous atherosclerosis. In the present study, we show that obese leptin receptor-deficient mice (db/db) lacking LDLR have a similar phenotype, even in the presence of elevated plasma leptin levels. We investigated the mechanism for the hyperlipidemia in obese LDLR(-/-) mice by comparing lipoprotein production and clearance rates in C57BL/6, ob/ob, LDLR(-/-) and ob/ob;LDLR(-/-) mice. Hepatic triglyceride production rates were equally increased ( approximately 1.4-fold, P<.05) in both LDLR(-/-) and ob/ob;LDLR(-/-) mice compared to C57BL/6 and ob/ob mice. LDL clearance was decreased ( approximately 1.3- fold, P<.01) to a similar extent in LDLR(-/-) and ob/ob;LDLR(-/-) mice compared to C57BL/6 and ob/ob controls. While VLDL clearance was delayed in LDLR(-/-) compared to C57BL/6 and ob/ob mice (2-fold, P<.001), this delay was exaggerated in ob/ob;LDLR(-/-) mice (3.8-fold, P<001). The VLDL clearance defects were due to decreased hepatic uptake compared to C57BL/6 (54% and 26% for LDLR(-/-) and ob/ob;LDLR(-/-), respectively, P<.001). When VLDL was collected from C57BL/6, ob/ob, LDLR(-/-), and ob/ob;LDLR(-/-) donors and injected into LDLR(-/-) recipient mice, counts remaining in the liver were 1.4-fold elevated in mice receiving LDLR(-/-) VLDL and 2-fold increased in mice receiving ob/ob;LDLR(-/-) VLDL compared to controls receiving C57BL/6 VLDL (P<.01). Thus, the increase in plasma lipoproteins in ob/ob;LDLR(-/-) mice is caused by delayed VLDL clearance. This appears to be due to defects in both the liver and the lipoproteins themselves in these obese mice.     

Diurnal variations of food consumption, plasma glucose and plasma insulin concentrations in lean and obese hyperglycaemic mice.

Diurnal variations in food consumption and plasma concentrations of glucose and insulin were determined at 3-hourly intervals in obese hyperglycaemic mice (C57BL/6J ob/ob) and lean mice (C57BL/6J+/+). In lean mice, food consumption and plasma insulin concentrations increased during the light period and were reduced during the dark period, whereas plasma glucose concentrations were maximal at the beginning of the light period and declined to a minimum during the early dark period. In ob/ob mice, the plasma glucose concentration declined temporarily at the beginning of both the light and the dark period and became elevated towards the ends of these periods, but there were no significant diurnal variations of food consumption or plasma insulin concentrations. These observations indicate differences in the diurnal regulation of glucose homeostasis in lean and ob/ob mice.     

Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes

Oxidative and nitrative stress responses resulting from inflammation exacerbate liver injury associated with nonalcoholic steatohepatitis (NASH) by inducing lipid peroxidation and protein nitration. The objective of this study was to investigate whether the anti-inflammatory properties of green tea extract (GTE) would protect against NASH by suppressing oxidative and nitrative damage mediated by proinflammatory enzymes. Obese mice (ob/ob) and their 5-week-old C57BL6 lean littermates were fed 0%, 0.5% or 1% GTE for 6 weeks (n=12-13 mice/group). In obese mice, hepatic lipid accumulation, inflammatory infiltrates and serum alanine aminotransferase activity were markedly increased, whereas these markers of hepatic steatosis, inflammation and injury were significantly reduced among obese mice fed GTE. GTE also normalized hepatic 4-hydroxynonenal and 3-nitro-tyrosine (N-Tyr) concentrations to those observed in lean controls. These oxidative and nitrative damage markers were correlated with alanine aminotransferase (P<.05; r=0.410-0.471). Improvements in oxidative and nitrative damage by GTE were also associated with lower hepatic nicotinamide adenine dinucleotide phosphate oxidase activity. Likewise, GTE reduced protein expression levels of hepatic myeloperoxidase and inducible nitric oxide synthase and decreased the concentrations of nitric oxide metabolites. Correlative relationships between nicotinamide adenine dinucleotide phosphate oxidase and hepatic 4-hydroxynonenal (r=0.364) as well as nitric oxide metabolites and N-Tyr (r=0.598) suggest that GTE mitigates lipid peroxidation and protein nitration by suppressing the generation of reactive oxygen and nitrogen species. Further study is warranted to determine whether GTE can be recommended as an effective dietary strategy to reduce the risk of obesity-triggered NASH.     

A newly synthetic chromium complex--chromium(phenylalanine)3 improves insulin responsiveness and reduces whole body glucose tolerance

Low-molecular-weight organic chromium complexes such as chromium picolinate are often used as dietary supplements to improve insulin sensitivity and to correct dyslipidemia. However, toxicity associated with such chromium compounds has compromised their therapeutic value. The aim of this study was to evaluate the impact of a newly synthesized complex of chromium with phenylalanine, Cr(pa)3 on insulin-signaling and glucose tolerance. Cr(pa)3 was synthesized by chelating chromium(III) with D-phenylalanine ligand in aqueous solution. In mouse 3T3-adipocytes, Cr(pa)3 augmented insulin-stimulated glucose-uptake as assessed by a radioactive-glucose uptake assay. At the molecular level, Cr(pa)3 enhanced insulin-stimulated phosphorylation of Akt in a time- and concentration-dependent manner without altering the phosphorylation of insulin receptor. Oral treatment with Cr(pa)3 (150 microg/kg/d, for six weeks) in ob/ob+/+ obese mice significantly alleviated glucose tolerance compared with untreated obese mice. Unlike chromium picolinate, Cr(pa)3 does not cleave DNA under physiological reducing conditions. Collectively, these data suggest that Cr(pa)3 may represent a novel, less-toxic chromium supplement with potential therapeutic value to improve insulin sensitivity and glycemic control in type II diabetes.     

Genetically obese C57BL/6 ob/ob mice respond normally to sympathomimetic compounds

The suggestion that defective thermoregulatory thermogenesis in the genetically obese (ob/ob) mouse is due to a low thermic response to noradrenaline has been investigated using both noradrenaline and the longer-acting sympathomimetic compounds, ephedrine and BRL 26830A. Below thermoneutrality (23.5°C) the metabolic rate of obese mice was lower than that of their lean littermates, whereas at a thermoneutral temperature (31°C) the metabolic rate of the obese nice was as high as that of lean mice. This confirms the view that the ob/ob mouse has defective thermoregulatory thermogenesis. However, in C57BL/6 mice, this defect is not due to a failure to respond to noradrenaline, because at 31°C the maximum thermic effects of noradrenaline, ephedrine and BRL 26830A were as high in obese as in lean mice and at 23.5°C they were higher in obese than in lean mice. Furthermore, the response of brown adipose tissue to β-adrenoceptor stimulation appears normal since noradrenaline caused a normal rise in brown adipose tissue temperature, and treatment with noradrenaline or BRL 26830A $\text{in}$$\text{vivo}$ caused a normal increase in GDP binding by brown adipose tissue mtiochondria. At 31°C propranolol depressed metabolic rate equally in lean and obese C57BL/6 mice, whereas at 23.5°C it depressed metabolic rate more in lean than obese mice. In contrast to C57BL/6 mice, Aston ob/ob mice showed a reduced thermic response to noradrenaline. These results suggest that defective thermoregulatory thermogenesis in the ob/ob mouse is primarily due to a reduced ability to raise sympathetic tone, but in some strains an additional failure in the thermic response to noradrenaline may develop.     

TOF-SIMS analysis of lipid accumulation in the skeletal muscle of ob/ob mice

Skeletal muscle lipid accumulation is associated with several chronic metabolic disorders, including obesity, insulin resistance (IR) and type 2 diabetes. The aim of this study is to evaluate whether static imaging time-of-flight-secondary-ion mass spectrometry (TOF-SIMS) equipped with a Bismuth-cluster ion source can be used for studying skeletal muscle lipid accumulation associated with obesity. Mouse gastrocnemius muscle tissues in 10-week-old obese ob/ob (n = 8) and lean wild-type C57/BL6 (n = 6) mice were analyzed by TOF-SIMS. Our results showed that signal intensities of fatty acids (FAs) and diacylglycerols (DAGs) were significantly increased in skeletal muscle of the obese ob/ob mice as compared to the lean wild-type mice. These differences were revealed through a global analytical approach, principal component analysis (PCA) of TOF-SIMS spectra, and ion-specific TOF-SIMS images. Region-of-interest (ROI) analysis showed that FA signal intensities within the muscle cell were significantly increased in ob/ob mice. Moreover, analysis of the ratio between different FA peaks revealed changes in monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs), which is in agreement with previous reports on obesity. These changes in FA composition were also reflected in the ratio of different DAGs or phosphatidylcholines (PCs) that contain different FA residues. Imaging TOF-SIMS together with PCA of TOF-SIMS spectra is a promising tool for studying skeletal muscle lipid accumulation associated with obesity.     

Defective activation by glucose of hepatic glycogen synthesis in the obese hyperglycaemic mouse.

The administration of an oral glucose load to 24 h-starved lean (+/?) male C57BL/6 mice produced a rapid, 7-fold increase in the rate of hepatic glycogen synthesis and a sustained activation of glycogen synthase. In contrast, glucose produced only a small (4.5-fold), short-lived increase in hepatic glycogen synthesis in genetically obese (ob/ob) mice and no activation of glycogen synthase.     

Insulin binding to liver nuclei from lean and obese mice is altered by dietary fat.

Insulin binding to the plasma membrane is known to be altered by modifying the membrane composition through dietary treatment. As insulin binding receptors are also present on nuclear membrane, this study was undertaken to investigate if specific binding of insulin to the liver nuclei is altered by diet. 8-wk-old female C57 B 6J lean and ob/ob mice were fed semipurified diets containing 20% (w/w) fat of either high or low polyunsaturated-to-saturated (P/S) fatty acid ratio for 4 wk. Liver nuclei were prepared, insulin binding was measured and nuclear phospholipids were isolated for lipid analysis. Insulin binding was highest in nuclei prepared from lean mice fed a high P/S diet. Specific binding of insulin to nuclei prepared from obese mice was also increased by the high P/S diet, but to a lesser extent compared to lean mice. Feeding a high P/S diet increased polyunsaturated fatty acid content of membrane phospholipids from both lean and ob/ob mice. Obese mice were characterized by higher levels of arachidonic acid and lower levels of linoleic acid in phosphatidylcholine. The present study establishes that insulin binding to liver nuclei is increased by feeding a high P/S diet, and that insulin binding to liver nuclei from obese mice is lower than from lean mice.     

Antiobesity effect of PEGylated conjugated linoleic acid on high-fat diet-induced obese C57BL/6J (ob/ob) mice: attenuation of insulin resistance and enhancement of antioxidant defenses

This study was designed to test that dietary conjugated linoleic acids (CLA) used in a mixture of cis-9,trans-11 and trans-10, cis-12 isomers (40% each in weight) coupled to poly(ethylene glycol) (PEG) as PEGylated CLA (PCLA) act as mediators inducing or inhibiting specific metabolic pathways in high-fat (HF)-fed obese C57BL/6J (ob/ob) mice. After an acclimatization period of 7 days, animals were given a normal (control) or HF diet, the latter being added either alone (HF) or with CLA, PEG or PCLA for 6 weeks. Although the food intakes were not different among the dietary groups, final body weights were significantly lower in the HF-PCLA group than in the HF group. Also the HF-PCLA diet strongly prevented the dramatic increase in blood low-density lipoprotein cholesterol observed with the HF diet, with no difference in high-density lipoprotein cholesterol between control, HF and HF-PCLA treatments. Furthermore, homeostasis model assessment levels showed a marked decrease in HF-PCLA-fed mice, preventing the increase found in mice fed the HF diet, and suggesting that PCLA lowered insulin resistance in HF-mice. The liver steatosis observed in mice fed the HF diet was also prevented by PCLA. Interestingly, the activity of mitochondrial glutathione peroxidase was increased by PCLA, which may enhance antioxidant defenses. Overall, PCLA exerted its beneficial effects through reduction of lipid accumulation and attenuation of insulin resistance induced by the HF diet in obese C57BL/6J (ob/ob) mice, which might confer to these products antiobesity properties in other species.     

Maintenance of adiponectin attenuates insulin resistance induced by dietary conjugated linoleic acid in mice

Conjugated linoleic acid (CLA) causes insulin resistance and hepatic steatosis in conjunction with depletion of adipokines in some rodent models. Our objective was to determine whether the maintenance of adipokines, mainly leptin and adiponectin, by either removing CLA from diets or using an adiponectin enhancer, rosiglitazone (ROSI), could attenuate CLA-induced insulin resistance. Male C57BL/6 mice were consecutively fed two experimental diets containing 1.5% CLA mixed isomer for 4 weeks followed by a diet without CLA for 4 weeks. CLA significantly depleted adiponectin but not leptin and was accompanied by hepatic steatosis and insulin resistance. These effects were attenuated after switching mice to the diet without CLA along with restoration of adiponectin. To further elucidate the role of adiponectin in CLA-mediated insulin resistance, ROSI was used in a subsequent study in male ob/ob mice fed either control (CON) or CLA diet. ROSI maintained significantly higher adiponectin levels in CON- and CLA-fed mice and prevented the depletion of epididymal adipose tissue and the development of insulin resistance. In conclusion, we show that insulin resistance induced by CLA may be related more to adiponectin depletion than to leptin and that maintaining adiponectin levels alone either by removing CLA or using ROSI can attenuate these effects.     

Effects of a novel Y5 antagonist in obese mice: combination with food restriction or sibutramine

Objective: To further address the function of the Y5 receptor in energy homeostasis, we investigated the effects of a novel spironolactone Y5 antagonist in diet-induced obese (DIO) mice. Methods and Procedures: Male C57BL/6 or Npy5r^−/− mice were adapted to high-fat (HF) diet for 6–10 months and were submitted to three experimental treatments. First, the Y5 antagonist at a dose of 10 or 30 mg/kg was administered for 1 month to DIO C57BL/6 or Npy5r^−/− mice. Second, the Y5 antagonist at 30 mg/kg was administered for 1.5 months to DIO C57BL/6 mice, and insulin sensitivity was evaluated using an insulin tolerance test. After a recovery period, nuclear magnetic resonance measurement was performed to evaluate body composition. Third, DIO mice were treated with the Y5 antagonist alone, or in combination with 10% food restriction, or with another anorectic agent, sibutramine at 10 mg/kg, for 1.5 months. Plasma glucose, insulin, and leptin levels, and adipose tissue weights were quantified. Results: The spironolactone Y5 antagonist significantly reduced body weight in C57BL DIO mice, but not in Npy5r^−/− DIO mice. The Y5 antagonist produced a fat-selective loss of body weight, and ameliorated obesity-associated insulin resistance in DIO mice. In addition, the Y5 antagonist combined with either food restriction or sibutramine tended to produce greater body weight loss, as compared with single treatment. Discussion: These findings demonstrate that the Y5 receptor is an important mediator of energy homeostasis in rodents.     

Stearoyl-CoA desaturase-1 deficiency attenuates obesity and insulin resistance in leptin-resistant obese mice

Obesity and adiposity greatly increase the risk for secondary conditions such as insulin resistance. Mice deficient in the enzyme stearoyl-CoA desaturase-1 (SCD1) are lean and protected from diet-induced obesity and insulin resistance. In order to determine the effect of SCD1 deficiency on various mouse models of obesity, we introduced a global deletion of the Scd1 gene into leptin-deficient ob/ob mice, leptin-resistant Agouti (A^y/a) mice, and high-fat diet-fed obese (DIO) mice. SCD1 deficiency lowered body weight, adiposity, hepatic lipid accumulation, and hepatic lipogenic gene expression in all three mouse models. However, glucose tolerance, insulin, and leptin sensitivity were improved by SCD1 deficiency only in A^y/a and DIO mice, but not ob/ob mice. These data uncouple the effects of SCD1 deficiency on weight loss from those on insulin sensitivity and suggest a beneficial effect of SCD1 inhibition on insulin sensitivity in obese mice that express a functional leptin gene.