Increased adipose tissue lipolysis after a 2-week high-fat diet in sedentary overweight/obese men

The purpose of this study was to determine if a high-fat diet would result in a higher lipolytic rate in subcutaneous adipose tissue than a lower-fat diet in sedentary nonlean men. Six participants (healthy males; 18-40 years old; body mass index, 25-37 kg/m²) underwent 2 weeks on a high-fat or well-balanced diet of similar energy content (approximately 6695 kJ) in randomized order with a 10-day washout period between diets. Subcutaneous abdominal adipose tissue lipolysis was determined over the course of a day using microdialysis after both 2-week diet sessions. Average interstitial glycerol concentrations (index of lipolysis) as determined using microdialysis were higher after the high-fat diet (210.8 ± 27.9 μmol/L) than after a well-balanced diet (175.6 ± 23.3 μmol/L; P = .026). There was no difference in adipose tissue microvascular blood flow as determined using the microdialysis ethanol technique. These results demonstrate that healthy nonlean men who diet on the high-fat plan have a higher lipolytic rate in subcutaneous abdominal adipose tissue than when they diet on a well-balanced diet plan. This higher rate of lipolysis may result in a higher rate of fat mass loss on the high-fat diet; however, it remains to be determined if this higher lipolytic rate in men on the high-fat diet results in a more rapid net loss of triglyceride from the abdominal adipose depots, or if the higher lipolytic rate is counteracted by an increased rate of lipid storage.     

二甲双胍对高脂饲养大鼠肝脏脂肪变的干预作用

目的:探讨胰岛素抵抗在非酒精性脂肪性肝发病中的作用及机制,观察二甲双胍对高脂饲养大鼠肝脏脂肪变的干预效果.方法:21只(?) Wistar大鼠分为3组,每组7只,普通饮食组(SD),高脂饮食组(HF),二甲双胍组(HF- Met)在高脂饮食的同时给予二甲双胍,共8wk.8 wk末处死大鼠,称量附睾脂肪,计算肝指数,生化方法测定ALT、AST、TG、TC、FFA、SOD和MDA.放免法测定空腹胰岛素,逆转录聚合酶链反应(RT-PCR)和ELISA法检测肝脏TNF-αmRNA和蛋白的表达,用葡萄糖输注率(GIR)来评价胰岛素敏感性,并观察肝组织病理变化.结果:与HF相比,HF-Met肝细胞脂肪变和小叶炎症明显减轻,肝指数、胰岛素、AST、ALT、TG、FFA显著下降(3.25±0.26 vs 4.29±0.12,33.37±8.34 vs 46.73±5.24,17.29±5.34 vs 43.48±6.21,4.10±2.47 vs 12.05±4.05,P<0.01;106.0±31.04 vs 141.37±24.87,48.31±16.11 vs 88.34±21.94,P<0.05)TNF-α的表达也显著下降,GIR增加(7.58±1.05 vs 6.31±1.28,P<0.05).结论:二甲双胍干预能明显改善高脂饲养大鼠的胰岛素抵抗,降低肝脏TG、FFA和TNF-α的表达,减轻肝脏脂肪变的程度,提示胰岛素增敏治疗可能是NAFLD防治的一种积极策略.     

Helianthus tuberosus(Jerusalem artichoke) tubers improve glucose tolerance and hepatic lipid profile in rats fed a high-fat diet

Objective:To analyze the effects of feeding Helianthus tuberosus(HT) tubers on glucose tolerance and lipid profile in rats fed a high-fat diet(HFD). Methods:A normal HFD or HFD including 10 w/w% HT tubers(HFD + HT) was fed to F334/Jcl rats. After 10 weeks,organ weights,glucose tolerance,and lipid profile were analyzed. Results:The body weight,liver weight,and epidermal fat content in the HFD group were higher than those of the normal group,and similar to those of the HFD + HT group. The oral glucose tolerance test at 10 weeks revealed that the blood glucose level 30 minutes after beginning the test in the HFD + HT group was significantly lower than that in the HFD group. Liver triglyceride and total cholesterol levels in the HFD + HT group were significantly lower than those in the HFD group. Fecal triglyceride and total cholesterol levels in the HFD + HT group were higher than those in the HFD group. Histological analyses revealed that fat and glycogen accumulation increased in the HFD group,but decreased in the HFD + HT group. Conclusions:These results indicate that HT tubers have anti-fatty liver effects based on improvements in glucose tolerance and the hepatic lipid profile.     

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.     

Muscle tissue in obesity with different distribution of adipose tissue. Effects of physical training

Obese men and women with the same body fat mass, as well as obese women in another study, were divided into groups with male or female type of body fat distribution, but again with similar body fat mass. The participants were examined with measurements of body composition, including muscle fiber distribution, as well as circulatory and metabolic variables before and after physical training under controlled conditions. Obese men had higher lean body mass, blood pressure, blood glucose and plasma insulin, C-peptide, cholesterol and triglyceride concentrations than age- and body fat-matched obese women. Obese women with male type of adipose tissue distribution showed the same differences (except cholesterol) in comparisons with women with female type of adipose tissue distribution. The women with male type obesity were also more insulin resistant in glucose clamp measurements, and had male type of muscle fiber distribution. Physical training in the group of obese men resulted in a decrease of body fat, a further increase of lean body mass, an increase of fast twitch, aerobic type, muscle fibres as well as lower plasma insulin, cholesterol and triglyceride concentrations and lower blood pressure. Obese women with male type distribution of adipose tissue responded to physical training essentially like men. The insulin sensitivity was improved to the same level as in obese women with female type of adipose tissue distribution. In contrast, the latter women showed an increase of body fat and no metabolic improvements after training. These results show that obese women with male type of body fat distribution also have male characteristics of muscle mass, morphology and function. It is suggested that the obesity complications associated with this condition are improved by physical training because of an adaptation to a negative energy balance, in combination with an improvement of insulin sensitivity of the muscle mass. In contrast, the failure of obese women with female type of adipose tissue distribution to adapt to a negative energy balance during physical training is probably explaining their failure to decrease body fat and to improve metabolism during physical training.     

Effects of a very-low-calorie diet on adrenergic responsiveness in human adipose tissue

Nineteen obese women were given a strictly-defined very-low-calorie diet for three weeks, and changes in adipose tissue lipolysis were studied using adrenergic drugs. The beta-receptor responsiveness was tested by isoprenaline. Before the diet, we found a negative relationship between basal value and isoprenaline-net effect on glycerol release; after the diet, its relationship disappeared, but the beta-stimulated level remained at a similar maximum. The alpha-receptor responsiveness was studied using clonidine, which significantly inhibits lipolysis; this effect was twice as high after the diet than before. Adrenaline-induced lipolysis was also studied; we found a dose-dependent response, and after a diet a negative linear relationship between basal and adrenaline net-lipolysis, so that adrenaline became antilipolytic for the high values of spontaneous lipolysis. We conclude that: (1) diet does not modify adipocyte-beta-receptor responsiveness, but it increases alpha-receptor responsiveness; (2) relationships between basal lipolysis and the lipolytic responsiveness of adrenergic receptors, which already exist with the spontaneous feeding, are enhanced by the hypocaloric diet, but in such a way that adipocyte-lipolysis remains within a given range; (3) we were unable to find any relationship between rate of weight loss and amplitude of adrenergic-receptor responsiveness.     

Influence of dietary fat on the lipid composition of perirenal adipose tissue in rats

The influence of dietary fat on the composition of perirenal adipose tissue was studied in Wistar rats fed three experimental semisynthetic, isocaloric diets containing different qualities of fat (olive oil, butter and medium chain triglycerides + corn oil). Under these experimental conditions, the saturation index reflects the percentage of fatty acids supplied by each diet; this index was highest in animals fed the diet containing butter and lowest in the group in which olive oil was the dietary fat source. The amount of linoleic acid (the major component of the diunsaturation index) supplied by the diet is directly paralleled by levels of this fatty acid in perirenal adipose tissue, whereas the monounsaturation index in adipose tissues, considered an indicator of the dietary supply of monounsaturated fatty acids in the rat, failed to show a clearly proportional relationship between intake and perirenal adipose tissue levels.     

The lipoprotein lipase activator, NO-1886, suppresses fat accumulation and insulin resistance in rats fed a high-fat diet

Abstract Aims/hypothesis. Fat balance is critical in the aetiology of obesity and related diseases. Lipoprotein lipase is of major importance in lipid metabolism. The aim of this study was to investigate the long-term effects of the lipoprotein lipase activator, NO-1886, on substrate utilisation, adiposity and insulin action in rats fed a high-fat diet.?Methods. Male, Sprague-Dawley rats were fed for 10 weeks on a chow diet or a high-fat diet with, or without, NO-1886 (50 mg · kg^–1· day^–1). Weight gain, fat accumulation and both hormone-sensitive and lipoprotein, lipase activities were measured. Insulin action was assessed by the euglycaemic hyperinsulinaemic clamp and metabolic rate/substrate utilisation by open-circuit respirometry.?Results. Compared with chow-fed controls, a high-fat diet increased weight gain, an effect lessened by NO-1886 [weight gain (g): chow, 37 ± 3, high-fat, 222 ± 9; high-fat + NO-1886, 109 ± 6, all groups differed p < 0.001]. A similar pattern existed for fat accumulation [visceral fat (g): chow, 35.9 ± 3.2; high-fat, 81.9 ± 6.6; high-fat + NO-1886, 52.3 ± 4.7, p < 0.01 high-fat vs the other groups]. A high-fat diet induced whole-body insulin resistance (clamp glucose infusion rate: 4.8 ± 1.3 mg · kg^–1· min^–1 vs 10.6 ± 1.1 for the chow group, p < 0.01) with NO-1886 lessening this effect (8.3 ± 0.5, p < 0.05 vs high-fat). The 24-h respiratory quotient was lower in the high-fat + NO-1886 group (0.825 ± 0.010) compared with high-fat alone (0.849 ± 0.004, p < 0.05). A high-fat diet increased lipoprotein and hormone-sensitive, lipase activities in epididymal fat, an effect not altered by NO-1886. In myocardium and skeletal muscle a high-fat diet lowered lipoprotein lipase activity, an effect lessened by NO-1886.?Conclusion/interpretation: Lipoprotein lipase activators could have potential benefits for the treatment of obesity by increasing fat utilisation. [Diabetologia (2000) 43: 875–880] Received: 11 January 2000 and in final revised form: 4 April 2000     

Effects of long-term high-sucrose and dexamethasone on fat depots, liver fat, and lipid fuel fluxes through the retroperitoneal adipose tissue and splanchnic area in rats

In affluent societies high caloric intake and chronic stress are currently associated with upper body fat. We investigated the effects of a high-sucrose (S) diet and dexamethasone (DEX) on fat depots (experiment 1) and lipid fuel fluxes (experiment 2) in male Wistar rats. In experiment 1, a liquid diet of commercial powdered milk containing 31% calories as carbohydrate or an isocaloric S diet (80% calories as carbohydrate) was offered to male rats. One half of the rats on each diet received a daily dose of 3 microg DEX in their diet. Intake was measured daily and body weight 3 times a week. Rats were killed after 7 weeks, and fat depot weights and carcass lipid were determined. In a second experiment, other rats received only the S diet with or without DEX. After 7 weeks, under pentobarbital anesthesia, arterial, portal, and iliolumbar vein blood was drawn, and the liver was extracted. Plasma concentration of triacylglycerides (TAG), nonesterified fatty acids (NEFA), glycerol (GOL), and lactate (L) and liver TAG were measured. Rats on the S diet ingested less and gained less weight. DEX treatment significantly reduced body weight gain. All fat depots as percentage of body weight were increased only in the S-DEX group. The S-DEX group had more liver TAG and less arterial NEFA and GOL than the S group. TAG determinations showed unexpected results: portal levels in the S-DEX group and iliolumbar levels in both groups were significantly higher than in the arterial plasma. This fact, together with high NEFA/GOL ratios in these veins, may signify incomplete TAG hydrolysis by lipoprotein lipase. L levels were higher in the S-DEX group and higher in arterial versus venous blood in both groups, indicating L uptake both in the splanchnic area and the retroperitoneal fat. These results show that, in rats, a long-term high-sucrose diet has peculiar effects on L turnover, and when associated with DEX, it also increases fat depots, induces liver steatosis, and, presumably, inhibits complete hydrolysis of TAG by lipoprotein lipase (LPL).     

Effects of short-term high-fat, high-energy diet on hepatic and myocardial triglyceride content in healthy men

CONTEXT: An association has been suggested between elevated plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride (TG) accumulation, and myocardial function. OBJECTIVE: Our objective was to investigate the effects of an elevation of plasma NEFA by a high-fat, high-energy (HFHE) diet on hepatic and myocardial TG accumulation, and on myocardial function. DESIGN: There were 15 healthy males (mean +/- sd age: 25.0 +/- 6.6 yr) subjected to a 3-d HFHE diet consisting of their regular diet, supplemented with 800 ml cream (280 g fat) every day. METHODS: (1)H-magnetic resonance spectroscopy was performed for assessing hepatic and myocardial TGs. Furthermore, left ventricular function was assessed using magnetic resonance imaging. RESULTS: The HFHE diet increased hepatic TGs compared with baseline (from 2.01 +/- 1.79 to 4.26 +/- 2.78%; P = 0.001) in parallel to plasma TGs and NEFA. Myocardial TGs did not change (0.38 +/- 0.18 vs. 0.40 +/- 0.12%; P = 0.7). The HFHE diet did not change myocardial systolic function. Diastolic function, assessed by dividing the maximum flow across the mitral valve of the early diastolic filling phase by the maximum flow of the atrial contraction (E/A ratio), decreased compared with baseline (from 2.11 +/- 0.39 to 1.89 +/- 0.33; P = 0.031). This difference was no longer significant after adjustment for heart rate (P = 0.12). CONCLUSIONS: Short-term HFHE diet in healthy males results in major increases in plasma TG and NEFA concentrations and hepatic TGs, whereas it does not influence myocardial TGs or myocardial function. These observations indicate differential, tissue-specific partitioning of TGs and/or fatty acids among nonadipose organs during HFHE diet.     

Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation

We recently reported that treatment with a pharmacologic dose of recombinant human growth hormone (GH) resulted in a significant loss of body fat and gain in lean tissue in HIV-infected patients with syndromes of fat accumulation. However, insulin-mediated glucose disposal decreased transiently after one month of GH therapy. The present paper focuses on the changes of hepatic carbohydrate and fat metabolism associated with GH treatment in the same subjects. We assessed hepatic insulin sensitivity under both fasting and hyperinsulinemic-euglycemic clamp conditions prior to and after one and six months of GH treatment (3 mg/day) in five patients using stable isotope tracer techniques. Indirect calorimetry, and measurements of lipid concentrations. Fasting endogenous glucose production (EGP) increased significantly at one month (12.0 +/- 0.7 to 14.9 +/- 0.9 micromol/kg/min, P < 0.03), and the increase was sustained at six months of GH treatment (14.0 +/- 1.1 micromol/kg/min, NS). This increase in EGP was driven in part by increased glucogenesis (GNG) (3.5 +/- 0.9 to 5.2 +/- 0.9 and 5.8 +/-1.2 micromol/kg/min, n = 4, P < 0.01 and P < 0.01 at one and six months, respectively); small changes in hepatic glycogenolysis also contributed. Sustained increases in lipolysis and progressive decreases in hepatic fractional de novo lipogenesis (DNL) and triglyceride concentrations occurred with GH treatment. These changes were accompanied by an improved lipid profile with a significant increase in HDL cholesterol and significant decreases in total and LDL cholesterol and triglyceride levels, the latter consistent with the decrease in hepatic DNL. During a hyperinsulinemic-euglycemic glucose clamp, EGP and GNG were markedly suppressed compared to the corresponding time points under fasting conditions, albeit less so when measured after one month of GH treatment. Thus, in HIV-infected patients with abnormal fat distribution, pharmacologic doses of GH improved the overall lipid profile, but worsened glucose homeostasis under both fasting and hyperinsulinemic conditions. The combined implications of these positive and negative metabolic effects for cardiovascular disease risk remain unknown.     

Effects of fenofibrate on lipid metabolism in adipose tissue of rats

The effect of fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, on body weight gain and on reduction of adipose tissue pads has been ascribed to increased fat catabolism in liver mainly through the induction of target enzymes involved in hepatic lipid metabolism. The aim of this study was to investigate whether peroxisome proliferator-activated receptor alpha activation also affects metabolic pathways in adipose tissue of rats treated with fenofibrate (100 mg/kg body weight) for 9 days. Fenofibrate lowered body weight gain and plasma triglyceride, total cholesterol, and high-density lipoprotein cholesterol but had no influence on food intake and on plasma glucose levels. The activity of lipoprotein lipase of treated animals decreased 50% in epididymal, 29% in retroperitoneal, and was not affected in the mesenteric fat pads. In this study, we show a 34% decrease in epididymal adipose tissue de novo lipogenesis by fenofibrate. The results demonstrate that insulin sensitivity of lipolysis is decreased in fenofibrate-treated rats which resulted in 30% higher rate of glycerol release when compared to the control group. These findings suggest that besides its effects on liver, fenofibrate exerts effects on lipid metabolism in adipose tissue which may contribute to decreasing adiposity.     

Effects of submaximal physical exercise on adipose tissue metabolism in man

In order to follow early metabolic adaptations in adipose tissue, which may lead to a decrease in fat cell size and body fat obtained by physical training, two sets of experiments were performed. Obese subjects and a control group exercised on a bicycle at two-thirds of maximal working capacity for one hour. Twenty-four hours thereafter, either on ad libitum diet, or on an isocaloric diet supplemented with calories corresponding to the expanded calories during the work load, an adipose tissue biopsy was taken and fat cell metabolism studied. In obese subjects on and ad libitum or on an isocaloric diet the lipolytic process was increased after the exercise but no significant effects were found on the rates of glucose metabolism. Furthermore, a relationship between cell surface and metabolism was found before, but not after, the work in all groups. No changes were seen in lipoprotein lipase activity. Obese subjects on a controlled diet showed a somewhat higher insulin and catecholamine responsiveness of adipocytes than was the case in the obese subjects on an ad libitum diet. This may well be due to the differences in carbohydrate intake, a factor of importance for hormonal responsiveness of fat cells. The increased basal lipolysis after exercise may be caused by the release of lipolytic hormones, and may well be the first sign of an adaption of the organism to diminish the fat stores as seen in physically trained subjects.     

Sex differences in the effect of high-fat diet feeding on rat white adipose tissue mitochondrial function and insulin sensitivity

Obesity-induced mitochondrial dysfunction in white adipose tissue (WAT) leads to a dysregulation of adipokine secretion, which is involved in insulin resistance development. Taking into account the sex differences previously found both in mitochondrial function and for the insulin sensitivity profile in different tissues, the aim of this study was to investigate whether a sex-dependent effect of a long-term high-fat diet (HFD) feeding exists on WAT mitochondrial function. Indeed, HFD effects on the levels of the key components of the insulin and adiponectin signaling pathways, and the consequences of these effects on the systemic profile of insulin sensitivity were also studied. Wistar rats of both sexes were fed a standard diet or an HFD. Serum markers of insulin sensitivity, protein, and mRNA levels of the main elements of the insulin and adiponectin signaling pathways, and the markers of mitochondrial function and biogenesis, were measured. Our results indicate that different physiological strategies are adopted by male and female rats in response to HFD. In this regard, HFD induced mitochondrial proliferation in males and mitochondrial differentiation in females, as well as a greater retroperitoneal WAT expandability capacity, which allows them to preserve a better insulin sensitivity profile than male rats for both control and HFD groups. Moreover, female WAT showed a decrease in adiponectin and insulin signaling pathway element levels. This sexual dimorphism suggests that there are different strategies for retroperitoneal WAT to maintain the energetic and metabolic homeostasis in response to HFD feeding.     

阻断肾素-血管紧张素系统对长期高脂喂养大鼠肝脂肪变性的影响

目的 观察长期高脂喂养诱导胰岛素抵抗状态大鼠肝脏脂肪变性与肝内血管紧张素原(AGT)、解偶联蛋白2(UCP-2)和转化生长因子β1(TGFβ1)表达的关系,并通过阻断肾素-血管紧张素系统(RAS)观察是否改善肝脂肪变性,探讨其作用机制.方法 40只大鼠分正常对照组、高脂组、血管紧张素转换酶抑制剂(ACEI)干预高脂组、血管紧张素Ⅱ受体阻滞剂(ARB)干预高脂组.正常血糖高胰岛素钳夹试验评价胰岛素敏感性,免疫组化和RT-PCR检测肝脏内AGT、UCP-2和TGFβ1蛋白及mRNA的表达,并检测血清脂质水平和肝内脂肪含量.结果 正常对照组、高脂组、ACEI干预高脂组、ARB干预高脂组稳态第2小时葡萄糖输注率分别为(11.22±1.45)、(6.22±1.02)、(8.08±1.13)、(8.16±1.26)mg·kg-1·min-1.高脂组血清学指标和肝内脂肪含量均高于正常对照组(P＜0.05),ACEI干预高脂组、ARB干预高脂组与高脂组比较,肝内脂肪含量降低(P＜0.01),脂肪变和纤维化减轻,肝内UCP-2和TGFβ1表达减少(P＜0.05).结论 阻断RAS可改善胰岛素抵抗,并可能通过下调肝内UCP-2和TGFβ1的表达,对长期高脂喂养大鼠肝脏有保护作用.