Resistance to body fat gain in 'double-muscled' mice fed a high-fat diet

OBJECTIVE: To determine if myostatin deficiency attenuates body fat gain with increased dietary fat intake. METHODS: Normal and myostatin-deficient mice were fed control (8-10 kcal %fat) and high-fat (HF) (45 kcal %fat) diets for a period of 8 weeks, starting at 2 months of age. Body composition, including percent body fat, lean mass, and fat mass, were measured using DXA. Serum adipokines were measured using a Beadlyte assay. RESULTS: Two-factor ANOVA revealed significant treatment x genotype interactions for body fat (g), percent body fat, and serum leptin. The HF diet significantly increased body fat, percent body fat, and serum leptin in normal mice but not in myostatin-deficient mice. CONCLUSION: Loss of myostatin function not only increases muscle mass in animal models but also attenuates the body fat accumulation that usually accompanies an HF diet.     

Regulatory effect of sense line diet on cholesterol and body weight in mice fed a high-fat diet

BACKGROUND/AIMS: Sense line diet (SLD) is a newly developed dietary functional food that is composed of a lot of herbs. The function of SLD is to help control weight. Although it is reported that each herb has effects on lipid metabolism and obesity, these effects are not the same as SLD. The aim of this study was therefore to investigate whether SLD combined with high fat (HF) diet can influence body weight and fat accumulation. METHODS: An experiment was conducted with 40 C57BL/6J mice with an initial body weight of about 16 g. Body weight was recorded every week, plasma levels of triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed at the end of the study. RESULTS: Weight increases in the 10 or 20% SLD group were significantly less than in the HF diet group (p < 0.05). Plasma triglyceride and LDL cholesterol levels were decreased by 52.1 and 34.2% in the 10% SLD group and 15.4 and 15.4% in the 20% SLD group, respectively, compared to the high-fat diet group. HDL cholesterol level was increased by 7.8% in the 10% SLD and by 54.9% in the 20% SLD group. CONCLUSIONS: Our findings indicate that SLD may be beneficial in the regulation of high-fat-diet-induced blood circulatory disorders as well as overweight.     

Effects of dietary fibers on weight gain, carbohydrate metabolism, and gastric ghrelin gene expression in mice fed a high-fat diet

Diets that are high in dietary fiber are reported to have substantial health benefits. We sought to compare the metabolic effects of 3 types of dietary fibers -- sugarcane fiber (SCF), psyllium (PSY), and cellulose (CEL) -- on body weight, carbohydrate metabolism, and stomach ghrelin gene expression in a high-fat diet-fed mouse model. Thirty-six male mice (C57BL/6) were randomly divided into 4 groups that consumed high-fat diet alone (HFD) or high-fat diet containing 10% SCF, PSY, and CEL, respectively. After baseline measurements were assessed for body weight, plasma insulin, glucose, leptin, and glucagon-like peptide 1 (GLP-1), animals were treated for 12 weeks. Parameters were reevaluated at the end of study. Whereas there was no difference at the baseline, body weight gains in the PSY and SCF groups were significantly lower than in the CEL group at the end of study. No difference in body weight was observed between the PSY and SCF animals. Body composition analysis demonstrated that fat mass in the SCF group was considerably lower than in the CEL and HFD groups. In addition, fasting plasma glucose and insulin and areas under the curve of intraperitoneal glucose tolerance test were also significantly lower in the SCF and PSY groups than in the CEL and HFD groups. Moreover, fasting plasma concentrations of leptin were significantly lower and GLP-1 level was 2-fold higher in the SCF and PSY mice than in the HFD and CEL mice. Ghrelin messenger RNA levels of stomach in the SCF group were significantly lower than in the CEL and HFD groups as well. These results suggest differences in response to dietary fiber intake in this animal model because high-fat diets incorporating dietary fibers such as SCF and PSY appeared to attenuate weight gain, enhance insulin sensitivity, and modulate leptin and GLP-1 secretion and gastric ghrelin gene expression.     

Retinoid X receptor gamma-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet

Retinoids, derivatives of vitamin A, induce hypertriglyceridemia through decreased clearance of very low-density lipoprotein by a lipoprotein lipase (LPL)-dependent pathway. The retinoid X receptor (RXR) gamma isotype, which is highly expressed in skeletal muscle, may be important in mediating the effects of retinoids on skeletal muscle metabolism and triglyceride (TG) clearance. RXRgamma-deficient (-/-) mice had lower fasting plasma TG levels compared with wild-type littermates (33.1 +/- 2.0 vs. 51.7 +/- 6.3 mg/dl, respectively; P < 0.05). Skeletal muscle LPL activity was higher in RXRgamma mice (18.7 +/- 2.2 vs. 13.3 +/- 1.3 nmol free fatty acids/min.g; P = 0.03), but LPL activity was not different in adipose and cardiac tissue, suggesting a specific effect of RXRgamma in skeletal muscle. In addition, when exposed to a 14-wk high-fat diet, RXRgamma -/- mice had less weight gain, which was entirely due to lower fat mass (11.9 +/- 1.8 vs. 14.4 +/- 1.1 g; P = 0.01), and leptin levels were also lower in the RXRgamma -/- mice (17.6 +/- 5.0 vs. 30.9 +/- 6.4 ng/ml; P = 0.03). These data suggest that RXRgamma -/- mice are resistant to gain in fat mass in response to high-fat feeding. This occurs, at least in part, through up-regulation of LPL activity in skeletal muscle. An understanding of the mechanisms governing the role of RXR in TG disposal and metabolism may lead to the rational design of RXR-selective agonists and antagonists that may be useful in common disorders such as dyslipidemia and obesity.     

Reduction in fat storage during chitin-chitosan treatment in mice fed a high-fat diet

OBJECTIVE: Chitin and chitosan are polymers containing more than 5000 acetylglucosamine and glucosamine units, respectively, and their molecular weights are over one million Daltons. The present study assessed the effects of chitin-chitosan on the activity of pancreatic lipase in vitro and on the degree of fat storage induced in mice by the oral administration of a high-fat diet for nine weeks. DESIGN: Mice were fed a high-fat diet and treated with chitin-chitosan for nine weeks. Experiments were also carried out to clarify whether or not chitin-chitosan inhibited pancreatic lipase activity in assay systems using triolein emulsified with lecithin, gum arabic or Triton X-100. RESULTS: Chitin-chitosan prevented the increase of body weight, hyperlipidaemia and fatty liver induced by a high-fat diet. Chitin-chitosan inhibited hydrolysis of triolein, emulsified with phosphatidylcholine, but not that of triolein emulsified with gum arabic and Triton X-100. These results suggest that the site of inhibitory action of chitin-chitosan may not be the enzyme but its substrate. CONCLUSION: The anti-obesity effects of chitin-chitosan in high-fat diet-treated mice might be partly due to the inhibition of intestinal absorption of dietary fat. Consequently, chitin-chitosan might cause improvement of the fatty liver and hyperlipidaemia in mice fed a high fat diet through inhibiting intestinal absorption of dietary fat.     

Increased atherosclerosis and vascular smooth muscle cell activation in AIF-1 transgenic mice fed a high-fat diet

Allograft inflammatory factor-1 (AIF-1) is a cytoplasmic, scaffold signal transduction protein constitutively expressed in inflammatory cells, but inducible in vascular smooth muscle cells (VSMCs) in response to injury or inflammatory stimuli. Although several basic science and population studies have reported increased AIF-1 expression in human and experimental atherosclerosis, a direct causal effect of AIF-1 expression on development of atherosclerosis has not been reported. The purpose of this study is to establish a direct relationship between AIF-1 expression and development of atherosclerosis. AIF-1 expression is detected VSMC in atherosclerotic lesions from ApoE(-/-) mice, but not normal arteries from wild-type mice. AIF-1 expression can be induced in cultured VSMC by stimulation with oxidized LDL (ox-LDL). Transgenic mice in which AIF-1 expression is driven by the G/C modified SM22 alpha promoter to restrict AIF-1 expression to VSMC develop significantly increased atherosclerosis compared with wild-type control mice when fed a high-fat diet (P=0.022). Cultured VSMC isolated from Tg mice demonstrated significantly increased migration in response to ox-LDL compared with matched controls (P<0.001). VSMC isolated from Tg mice and cultured human VSMC which over express AIF-1 demonstrated increased expression of MMP-2 and MMP-9 mRNA and protein and increased NF-κB activation in response to ox-LDL as compared with wild-type control mice. VSMC which over express AIF-1 have significantly increased uptake of ox-LDL, and increased CD36 expression. Together, these data suggest a strong association between AIF-1 expression, NF-κB activation, and development of experimental atherosclerosis.     

Myeloid-specific deletion of SIRT1 increases hepatic steatosis and hypothalamic inflammation in mice fed a high-fat diet

Obesity-induced fatty liver disease is associated with increased hypothalamic inflammation. Previous reports have demonstrated that the deletion of SIRT1 in hepatocytes increases hepatic steatosis and inflammation. Using myeloid cell-specific SIRT1 knockout (KO) mice, we investigated whether ablation of SIRT1 in macrophages plays a role in regulating hepatic steatosis and hypothalamic inflammation. When challenged with a high-fat diet (HFD) for 24 weeks, hyperleptinemia, hyperinsulinemia, hepatic steatosis and macrophage infiltrations in HFD-fed KO mice were increased compared with HFD-fed WT mice. Hypothalamic expression levels of iba1 were increased in HFD-fed KO mice compared with HFD-fed WT mice. In particular, the expression levels of choline acetyltransferase were decreased in the hypothalamus of HFD-fed KO mice compared with HFD-fed WT mice. Thus, our findings suggest that SIRT1 plays a key role for hepatic steatosis and hypothalamic inflammation and that anti-inflammatory effect of SIRT1 may be important for the prevention of obesity-induced metabolic syndromes.     

Ileal transposition surgery attenuates the increased efficiency of weight gain on a high-fat diet

High-fat diets enhance weight gain in rats and humans. Ileal transposition surgery (IT) causes long-term weight loss on ad libitum food intake. This study was designed to study the effect of high-fat diets on weight loss following ileal transposition surgery. We weight matched 40 rats, performed IT or sham IT, and fed defined high-carbohydrate (12 percent kcal as fat) or high-fat (45 percent kcal as fat) diets for 15 weeks postsurgery (N = 10/group, data are means +/- s.e.m.). Overall, IT rats ate less than sham IT rats, 9587 +/- 304 v. 10,615 +/- 356 kcal (39.6 +/- 1.2 v. 43.8 +/- 1.5 MJ) (P less than 0.01), and gained less weight (-14 +/- 7.8 v. 46 +/- 13.7 g) (P less than 0.01). Sham IT rats had similar food intakes on the two diets, but body weights were increased on the high-fat diet. However, the IT rats on the high-fat diet did not gain more weight or have higher efficiency of weight gain than did the IT rats on the high-carbohydrate diet. We conclude that ileal transposition attenuates the increased efficiency of weight gain usually associated with consumption of a high-fat diet. The mechanisms of this decreased metabolic efficiency are unclear.     

Polyunsaturated fatty acids of marine origin induce adiponectin in mice fed a high-fat diet

Aims/hypothesis Diets rich in n-3 polyunsaturated fatty acids, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against insulin resistance and obesity in rodents and increase insulin sensitivity in healthy humans. We tested whether the anti-diabetic effects of EPA and DHA involve enhanced production of the endogenous insulin sensitiser, adiponectin. Methods We studied the effects, in an obesity-promoting high-fat diet, of partial replacement of vegetable oils by EPA/DHA concentrate (6% EPA, 51% DHA) over a 5-week period in adult male C57BL/6J mice that either had free access to food or had their food intake restricted by 30%. At the end of the treatment, systemic markers of lipid and glucose metabolism and full-length adiponectin and leptin were measured. Adiponectin (Adipoq) and leptin (Lep) gene expression in dorsolumbar and epididymal white adipose tissue (WAT) and isolated adipocytes was quantified and adipokine production from WAT explants evaluated. Results In mice with free access to food, plasma triacylglycerols, NEFA, and insulin levels were lower in the presence of EPA/DHA, while glucose and leptin levels were not significantly altered. Food restriction decreased plasma triacylglycerols, glucose, insulin and leptin, but not adiponectin. EPA/DHA increased plasma adiponectin levels, independent of food intake, reflecting the stimulation of Adipoq expression in adipocytes and the release of adiponectin from WAT, particularly from epididymal fat. Expression of Lep and the release of leptin from WAT, while being extremely sensitive to caloric restriction, was unaltered by EPA/DHA. Conclusions/interpretation Intake of diets rich in EPA and DHA leads to elevated systemic concentrations of adiponectin, largely independent of food intake or adiposity and explain, to some extent, their anti-diabetic effects.     

大蒜素对高脂饮食ApoE－/－小鼠动脉粥样硬化形成的影响

目的观察大蒜素对高脂饮食诱导的ApoE~(-/-)小鼠巨噬细胞泡沫化及动脉粥样硬化形成的影响,并从清道夫受体调控的角度探讨其相关的作用机制。方法 6周雄性ApoE~(-/-)小鼠随机分为4组:正常饮食组、高脂饮食组、高脂饮食+低剂量大蒜素组、高脂饮食+高剂量大蒜素组。采用血脂检测试剂盒测定小鼠血脂水平;使用油红O染色法观察小鼠主动脉根部斑块形成面积和腹腔巨噬细胞泡沫化情况;Western blot法检测腹腔巨噬细胞中清道夫受体SR-A和CD36表达以及JNK和p38激酶磷酸化水平。结果大蒜素可呈剂量依赖性降低高脂饮食小鼠总胆固醇、甘油三酯及低密度脂蛋白胆固醇的水平(P0.05),并显著减少主动脉根部斑块面积以及腹腔巨噬细胞泡沫化的形成(P0.05)。Western blot结果显示大蒜素不仅抑制高脂饮食所诱导的腹腔巨噬细胞中SR-A和CD36表达的增加(P0.05),还能够显著减少JNK和p38激酶磷酸化水平。结论大蒜素减少SR-A和CD36表达,并抑制JNK和p38激酶激活,从而发挥抗泡沫化和动脉粥样硬化的作用。     

Vascular dysfunction and impaired insulin signaling in high-fat diet fed ovariectomized mice

The metabolic syndrome, characterized by conditions such as obesity and insulin resistance, is more prevalent in postmenopausal women than in premenopausal women, and increases the risk of cardiovascular disease and type 2 diabetes. The main objective of the present study was to investigate the combined effects of ovariectomy (OVX) and high-fat diet (HFD) on metabolic parameters, vascular function and glucose homeostasis in mice. After OVX or sham operation (Sham), mice were fed with either a normal diet (ND) or a HFD. Mice were divided into ND + Sham, ND + OVX, HFD + Sham, and HFD + OVX groups. After 4 weeks, HFD + OVX mice developed marked increases in body weight and plasma insulin levels, but not blood glucose levels. The area under the glucose tolerance curve (Δ AUC_glucose) following an oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR) revealed that HFD + OVX mice had higher values than any other group. Concomitantly with these metabolic disturbances, decreased tail skin blood flow and augmented tail skin flushing, a marker of hot flashes, were observed in HFD + OVX mice. These vascular modulations likely result from vasomotor dysfunction. Furthermore, we investigated whether OVX and HFD affect the insulin signaling pathway in mice. Insulin-induced Akt phosphorylation in the livers of HFD + OVX mice was significantly downregulated compared with ND + Sham and HFD + Sham mice. Thus, the HFD + OVX mice used in the present study constitute an experimental animal model of postmenopausal metabolic syndrome. Herein, we provide experimental evidence that vascular dysfunction and impaired insulin signaling may contribute to the pathogenesis of postmenopausal metabolic syndrome.     

Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet

Atherosclerosis is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL (P<0.01 versus wild-type mice). To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice 4% cholesterol/10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61+/-2% of aorta in the LDLR KO mice, but only 36+/-3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice). Expression of redox-sensitive NF-kappaB and the inflammatory marker CD68 in LDLR KO mice was increased (P<0.01 versus wild-type mice), but not in the double KO mice. On the other hand, antiinflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (P<0.01 versus wild-type mice), but not in the double KO mice. Endothelial nitric oxide synthase expression was also preserved in the double KO mice. The proinflammatory signal MAPK P38 was activated in the LDLR KO mice, and LOX-1 deletion reduced this signal. In conclusion, LOX-1 deletion sustains endothelial function leading to a reduction in atherogenesis in association with reduction in proinflammatory and prooxidant signals.     

Ezetimibe decreases SREBP-1c expression in liver and reverses hepatic insulin resistance in mice fed a high-fat diet

Ezetimibe inhibits intestinal cholesterol absorption, thereby reducing serum cholesterol. Recent studies suggest that ezetimibe affects liver steatosis and insulin resistance. We investigated the impact of ezetimibe on insulin sensitivity and glucose metabolism in C57BL/6 mice. We analyzed 4 mouse groups fed the following diets: normal chow (4% fat) for 12 weeks, normal chow for 10 weeks followed by normal chow plus ezetimibe for 2 weeks, high-fat chow (32% fat) for 12 weeks, and high-fat chow for 10 weeks followed by high-fat chow plus ezetimibe for 2 weeks. In the normal chow + ezetimibe group, ezetimibe had no impact on body weight, fat mass, lipid metabolism, liver steatosis, glucose tolerance, or insulin sensitivity. In the high-fat chow + ezetimibe group, ezetimibe had no impact on body weight or fat mass but significantly decreased serum low-density lipoprotein cholesterol, triglyceride, and glutamate pyruvate transaminase levels; liver weight; hepatic triglyceride content; and hepatic cholesterol content and increased the hepatic total bile acid content. In association with increases in IRS-2 and Akt phosphorylation, ezetimibe ameliorated hepatic insulin resistance in the high-fat chow + ezetimibe group, but had no effect on insulin sensitivity in primary cultured hepatocytes. A DNA microarray and Taqman polymerase chain reaction revealed that ezetimibe up-regulated hepatic SREBP2 and SHP expression and down-regulated hepatic SREBP-1c expression. SHP silencing mainly in the liver worsened insulin resistance, and ezetimibe protected against insulin resistance induced by down-regulation of SHP. Ezetimibe down-regulated SREBP-1c in the liver and reversed hepatic insulin resistance in mice fed a high-fat diet.     

Dietary supplementation of tetradecylthioacetic acid increases feed intake but reduces body weight gain and adipose depot sizes in rats fed on high-fat diets

Aim: The pan-peroxisome proliferator-activated receptor (PPAR) ligand and fatty acid analogue tetradecylthioacetic acid (TTA) may reduce plasma lipids and enhance hepatic lipid metabolism, as well as reduce adipose tissue sizes in rats fed on high-fat diets. This study further explores the effects of TTA on weight gain, feed intake and adipose tissue functions in rats that are fed a high-fat diet for 7 weeks.
Methods: The effects on feed intake and body weight during 7 weeks' dietary supplement with TTA (∼200 mg/kg bw) were studied in male Wistar rats fed on a lard-based diet containing ∼40% energy from fat. Adipose tissue mass, body composition and expression of relevant genes in fat depots and liver were measured at the end of the feeding.
Results: Despite higher feed intake during the final 2 weeks of the study, rats fed on TTA gained less body weight than lard-fed rats and had markedly decreased subcutaneous, epididymal, perirenal and mesenteric adipose depots. The effects of TTA feeding with reduced body weight gain and energy efficiency (weight gain/feed intake) started between day 10 and 13. Body contents of fat, protein and water were reduced after feeding lard plus TTA, with a stronger decrease in fat relative to protein. Plasma lipids, including Non-Esterified Fatty Acids (NEFA), were significantly reduced, whereas fatty acid β-oxidation in liver and heart was enhanced in lard plus TTA-fed rats. Hepatic UCP3 was expressed ectopically both at protein and mRNA level (>1900-fold), whereas Ucp1 mRNA was increased ∼30-fold in epididymal and ∼90-fold in mesenteric fat after lard plus TTA feeding.
Conclusion: Our data support the hypothesis that TTA feeding may increase hepatic fatty acid β-oxidation, and thereby reduce the size of adipose tissues. The functional importance of ectopic hepatic UCP3 is unknown, but might be associated with enhanced energy expenditure and thus the reduced feed efficiency.     

Exercise training does not reduce hyperlipidemia in pigs fed a high-fat diet

The pig is often used as a model for studying lipoprotein metabolism as it relates to human atherosclerosis, but few studies have examined the complete lipoprotein profile and related enzymes in swine ingesting an atherogenic diet. We examined whether exercise training would moderate the effects of an atherogenic diet on lipoproteins and lipoprotein lipase (LPL) activity in miniature swine. Male (n = 30) and female (n = 32) swine were initially divided into 2 dietary groups: one consumed low-fat (8%) pig chow, and one consumed pig chow supplemented with 2% cholesterol, 17.1% coconut oil, 2.3% corn oil, and.7% sodium cholate (46% kcal from fat). Following 30 days on the diets, pigs from each diet group were further divided into sedentary and exercise trained subgroups, each cell with 6 to 8 pigs. Training occurred 5 days per week on a treadmill in which the intensity and duration were progressively increased during the 16- to 20-week training period to 75 minutes of aerobic running per session. A 4-way analysis of variance (ANOVA) with repeated measures on time indicated that at the conclusion of the study the atherogenic diet caused significantly (P <.05) increased cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and subfractions, low-density lipoprotein cholesterol (LDL-C) and subfractions, and LPL activity in both genders. For cholesterol, TG, HDL-C, HDL(2)-C, LDL-C, LDL(1&2)-C, and hepatic lipase, the female response to the diet was exaggerated compared to the male response. Exercise training produced no group differences or interactions on any lipoprotein variable. These results suggest that an atherogenic diet has a greater impact on the lipoproteins of female miniature swine than males. Furthermore, under the conditions of this study, exercise training does not moderate the effects of an atherogenic diet on lipoproteins.     

Skeletal muscle oxidative capacity in rats fed high-fat diet.

OBJECTIVE: To investigate whether young rats respond to high-fat feeding through changes in energy efficiency and fuel partitioning at the level of skeletal muscle, to avoid obesity development. In addition, to establish whether the two mitochondrial subpopulations, which exist in skeletal muscle, ie subsarcolemmal and intermyofibrillar, are differently affected by high-fat feeding. DESIGN: Weaning rats were fed a low-fat or a high-fat diet for 15 days. MEASUREMENTS: Energy balance and lipid partitioning in the whole animal. State 3 and state 4 oxygen consumption rates in whole skeletal muscle homogenate. State 3 and state 4 oxygen consumption rates, membrane potential and uncoupling effect of palmitate in subsarcolemmal and intermyofibrillar mitochondria from skeletal muscle. RESULTS: Rats fed a high-fat diet showed an increased whole body lipid utilization. Skeletal muscle NAD-linked and lipid oxidative capacity significantly increased at the whole-tissue level, due to an increase in lipid oxidative capacity in subsarcolemmal and intermyofibrillar mitochondria and in NAD-linked activity only in intermyofibrillar ones. In addition, rats fed a high-fat diet showed an increase in the uncoupling effect of palmitate in both the mitochondrial populations. CONCLUSIONS: In young rats fed a high-fat diet, skeletal muscle contributes to enhanced whole body lipid oxidation through an increased mitochondrial capacity to use lipids as metabolic fuels, associated with a decrease in energy coupling.