Swimming's prevention of ovariectomy-induced obesity through activation of skeletal-muscle PPARα

Ovariectomy leads to weight gain primarily in the form of adipose tissue in rodents. The authors investigated whether swimming improves ovariectomy-induced obesity through activation of peroxisome proliferator-activated receptor α (PPARα) in the skeletal muscle of female ovariectomized (OVX) mice, an animal model of postmenopausal women. Female mice were randomly divided into 3 groups (n=8/group): a sedentary sham-operated group, a sedentary OVX group, and a swim-trained OVX group. After mice were subjected to swim training or kept sedentary for 6 wk, the authors studied the effects of swimming on not only bodyweight gain, white adipose tissue (WAT) mass, adipocyte size, and skeletal-muscle lipid accumulation but also the expression of skeletal-muscle PPARα target genes. Sedentary OVX mice had significantly higher body weight and WAT than sedentary sham mice. However, swim training reduced body-weight gain, WAT mass, and adipocyte size of OVX mice. Swim-trained OVX mice had significantly lower levels of serum triglycerides and total cholesterol than sedentary OVX mice. Lipid accumulation in skeletal muscle was also markedly decreased by swimming. Concomitantly, swim training significantly increased mRNA levels of skeletal-muscle PPARα and its target enzymes, as well as uncoupling protein 3 (UCP3) responsible for fatty-acid oxidation. These results suggest that swimming can effectively prevent weight gain, adiposity, adipocyte hypertrophy, and lipid disorders caused by ovariectomy, in part through the activation of PPARα and UCP3, in the skeletal muscle of female mice and may contribute to the alleviation of metabolic syndrome, including obesity, hyperlipidemia, and Type 2 diabetes in postmenopausal women.     

Retinoic acid as cause of cell proliferation or cell growth inhibition depending on activation of one of two different nuclear receptors

Retinoic acid can combine with the nuclear retinoic acid receptor (RAR), leading to cell growth inhibition, as in certain tumors. Retinoic acid can also bind to the orphan nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta), resulting in stimulation of cell growth and inhibition of apoptosis. To bind to RAR, retinoic acid is carried into the nucleus by the cytosolic cellular retinoic acid-binding protein-II; to bind to PPAR beta/delta, it is transported into the nucleus by the cytosolic fatty acid-binding protein 5.     

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.     

沙棘提取物对猪脂肪中部分脂肪代谢相关基因表达的影响

目的研究早期断奶仔猪喂饲沙棘提取物对脂肪组织中部分脂肪代谢相关基因表达的影响及其机制。方法选用(28±2)日龄东北民猪16头,随机分为对照组和试验组。试验组仔猪饲料中添加沙棘提取物(1000mg/kg),喂饲28d后改成基础饲粮,D180屠宰取样,RT-PCR方法检测猪脂肪组织中过氧化物酶增殖剂激活受体α(PPARα)、γ(PPARγ)、乙酰辅酶A氧化酶(ACO)和脂肪酸合成酶(FAS)的基因表达。结果早期喂饲沙棘提取物可使(1)腹脂和皮脂中PPARα和ACO的mRNA表达均增加;(2)腹脂中PPARγmRNA表达降低,腹脂和皮脂中FASmRNA表达均降低。结论断奶仔猪早期喂饲沙棘提取物可在转录水平调控脂肪代谢相关基因的表达,这可能是减少猪体内脂肪沉积和改善猪肉品质的机制之一。     

Molecular mechanisms of alcoholic fatty liver: role of peroxisome proliferator-activated receptor alpha

Normal function of the peroxisome proliferator-activated receptor alpha (PPARα) is crucial for the regulation of hepatic fatty acid metabolism. Fatty acids serve as ligands for PPARα, and when fatty acid levels increase, activation of PPARα induces a battery of fatty acid–metabolizing enzymes to restore fatty acid levels to normal. Hepatic fatty acid levels are increased during ethanol consumption. However, results of in vitro work showed that ethanol metabolism inhibited the ability of PPARα to bind DNA and activate reporter genes. This observation has been further studied in mice. Four weeks of ethanol feeding of C57BL/6J mice also impairs fatty acid catabolism in liver by blocking PPARα-mediated responses. Ethanol feeding decreased the level of retinoid X receptor alpha (RXRα) as well as the ability of PPARα/RXR in liver nuclear extracts to bind its consensus sequence, and the levels of mRNAs for several PPARα-regulated genes were reduced [long-chain acyl coenzyme A (acyl-CoA) dehydrogenase and medium-chain acyl-CoA dehydrogenase] or failed to be induced (acyl-CoA dehydrogenase, liver carnitine palmitoyl-CoA transferase I, very long-chain acyl-CoA synthetase, very long-chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals. Consistent with this finding, ethanol feeding did not induce the rate of fatty acid beta-oxidation, as assayed in liver homogenates. Inclusion of WY14,643, a PPARα agonist, in the diet restored the DNA-binding activity of PPARα/RXR, induced mRNA levels of several PPARα target genes, stimulated the rate of fatty acid beta-oxidation in liver homogenates, and prevented fatty liver in ethanol-fed animals. Blockade of PPARα function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by WY14,643.     

Conjugated linoleic acid persistently increases total energy expenditure in AKR/J mice without increasing uncoupling protein gene expression

AKR/J mice fed a high fat diet were treated with a 1% (1 g/100 g) admixture of conjugated linoleic acids (CLA) for 5 wk and compared with control mice. Body weights, energy intakes and energy expenditure (EE) determined by indirect calorimetry were measured weekly. CLA treatment reduced adipose depot weights by approximately 50% but had no significant effects on either body weight or energy intake. CLA increased EE persistently by an average of 7.7% throughout the 5-wk experiment. This greater EE, despite no difference in energy intake, was sufficient to account for the lower body fat stores in the CLA-treated mice. De novo fatty acid biosynthesis in adipose tissue, measured by incorporation of deuterium-labeled water, was not decreased by CLA treatment and therefore did not explain the lower adipose lipid in these mice. Expression of uncoupling protein (UCP) in skeletal muscle, white adipose tissue and kidney was not affected by CLA treatment. In brown adipose tissue, UCP1 expression was not affected by CLA treatment. However, UCP2 expression, although quite low, was significantly greater in CLA-fed mice. We conclude that CLA acts to reduce body fat stores by chronically increasing metabolic rate. This effect on metabolic rate is likely not due to increased UCP gene expression. Furthermore, the reduced body fat is not due to decreased de novo fatty acid synthesis in white adipose tissue.     

Obesity in insulin receptor substrate-2-deficient mice: disrupted control of arcuate nucleus neuropeptides

OBJECTIVE: Disturbances in insulin signaling have been shown to induce obesity and/or hyperphagia in brain insulin receptor or insulin receptor substrate-2 (IRS-2) knockout (KO) mice. This study aimed to examine the central and peripheral mechanisms underlying the phenotype in IRS-2 KO mice. RESEARCH METHODS AND PROCEDURES: We measured the histological characterization of adipose tissues, mRNA levels of pro-opiomelanocortin, agouti-related protein, and neuropeptide Y in the hypothalamus and uncoupling proteins (UCPs) in peripheral tissues of IRS-2 KO mice. RESULTS: Female IRS-2 KO mice showed increased daily food intake. Body weight and adiposity were increased in both sexes, although these differences were more pronounced in female than in male IRS-2 KO mice. Both male and female IRS-2 KO mice showed decreased UCP1 mRNA expression in brown adipose tissue with defective thermoregulation, and UCP2 mRNA expression was increased in the white adipose tissue of female knockout mice. Furthermore, arcuate nucleus mRNA expression of pro-opiomelanocortin, was decreased in both male and female IRS-2 KO mice, whereas expression of agouti-related protein and neuropeptide Y were increased in female IRS-2 KO mice. DISCUSSION: In IRS-2 KO mice, disrupted control of hypothalamic neuropeptide levels and UCP mRNA expression may contribute to the development of obesity.     

Seaweed carotenoid, fucoxanthin, as a multi-functional nutrient

Fucoxanthin has a unique structure including an unusual allenic bond and 5, 6-monoepoxide in its molecule. We found that abdominal white adipose tissue (WAT) weights of rats and mice fed fucoxanthin were significantly lower than those fed a control diet. The daily intake of fucoxanthin in mice also caused a significant reductions of body weight. Clear signals of uncoupling protein 1 (UCP1) and its mRNA were detected by Western and Northern blot analyses in abdominal WAT in mice fed fucoxanthin, although there is little expression of UCP1 in WAT in mice fed a control diet. UCP1 expression in WAT by fucoxanthin intake leads to oxidation of fatty acids and heat production in WAT mitochondria. Substrate oxidation can directly reduce WAT in animals. Fucoxanthin intake also significantly reduced blood glucose and plasma insulin. Furthermore, feeding fucoxanthin significantly increased the level of hepatic docosahexaenoic acid (DHA), a most important n-3 functional polyunsaturated fatty acid in biological systems. These multi-functionalities of fucoxanthin indicate that it is an important bioactive carotenoid that is beneficial for the prevention of the metabolicsyndrome.     

Olive oil feeding up-regulates uncoupling protein genes in rat brown adipose tissue and skeletal muscle

BACKGROUND: Some nutrients, such as carotenoids, retinoic acid, and certain types of fatty acids, increase thermogenic capacity. OBJECTIVE: The influence of 4 dietary lipid sources (olive oil, sunflower oil, palm oil, and beef tallow) on the content of uncoupling proteins 1, 2, and 3 (UCP1, UCP2, and UCP3) and their messenger RNA (mRNA) expression in several tissues of rats was compared. DESIGN: Wistar rats were randomly divided into 4 groups and fed ad libitum diets containing 40% of energy as fat. UCP1, UCP2, and UCP3 mRNA and protein were assessed by Northern blot and Western blot, respectively. Oxygen consumption in tissues was measured by polarography. Total-body oxygen consumption was assessed in an open-circuit chamber system. Circulating fuels (fatty acids and glucose) and hormones (triiodothyronine, thyroxine, corticosterone, and insulin) were measured. RESULTS: Olive oil feeding induced the highest UCP1, UCP2, and UCP3 mRNA expression in interscapular brown adipose tissue. An analogous effect was observed in gastrocnemius muscle UCP3 mRNA. No significant differences were observed in perirenal white adipose tissue UCP2 mRNA. Changes in mRNAs were not accompanied by close changes in the protein content of UCPs and were not associated with changes in adipose tissue oxygen consumption. Nevertheless, total-body oxygen consumption was higher in rats fed olive oil than in those fed the other 3 diets. No significant differences were found in body and tissue weights or in serum indexes. CONCLUSION: Olive oil induced an up-regulating effect on UCP mRNA that was probably not mediated by systemic metabolic changes, but rather related to a local effect on interscapular brown adipose tissue and skeletal muscle.     

Body fat accumulation is greater in rats fed a beef tallow diet than in rats fed a safflower or soybean oil diet

The effects of dietary fats , consisting of different fatty acids, on body fat accumulation and uncoupling protein (UCP) in interscapular brown adipose tissue were studied in rats. Metabolisable energy in experimental diets based on safflower oil, soybean oil or beef tallow was measured strictly (experiment 1). Male Wistar rats were then meal-fed an isoenergetic diet for 8 weeks (experiment 2). Each group of rats showed the same weight gain during the 8-week experimental period. Carcass fat content was greater in rats fed the beef tallow diet than in those fed the with the safflower or soybean oil diets, whereas the weight of abdominal adipose tissue was the same for all three dietary groups. Gene expression of UCP1 and the UCP content of the interscapular brown adipose tissue was lower in the beef tallow diet group than in the other dietary groups. A negative correlation was observed between carcass fat content and n-6 unsaturated fatty acid content in dietary fats. These results suggest that the greater body fat accumulation in rats fed the beef tallow diet results from lower expression of UCP1 mRNA and lower UCP content in brown adipose tissue. n-6 Polyunsaturated fatty acids may be the most effective fatty acids in limiting body fat.     

Dietary conjugated linoleic acid differentially alters fatty acid composition and increases conjugated linoleic acid content in porcine adipose tissue

Conjugated linoleic acids (CLA) have been shown to decrease body fat content in pigs. It is possible that feeding pigs diets rich in CLA may increase carcass lipid CLA to levels that could provide health benefits when included as a part of a healthy diet. Therefore, the aim of the present study was to determine whether dietary CLA supplementation has any effect on the fatty acid composition of subcutaneous and intramuscular adipose tissue in pigs. Thirty-five female cross bred (Large White x Landrace) pigs (initial weight 57.2 kg and initial P2 back fat 11.5 mm) were used in the present study. Pigs were housed individually and randomly allocated to one of six dietary treatments (0.00, 1.25, 2.50, 5.00, 7.50 and 10.00 g CLA55 (55 g CLA isomers/100 g total fatty acids; Natural Lipids Ltd, Hovdebygda, Norway)/kg) and fed their respective diets for 8 weeks. Twelve CLA isomers in the diet and in pig tissue lipids were separated by Ag+-HPLC. CLA was incorporated at fivefold higher levels in subcutaneous fat as compared with intramuscular fat and in a dose-dependant manner. Overall, the transfer efficiency of CLA was maximized at 5.00 g CLA55/kg. However, there was clear selectivity in the uptake or incorporation of cis,trans-9,11 isomer over the trans,cis-10,12 isomer. In general, CLA supplementation produced significant changes in skeletal muscle and adipose tissue fatty acid composition, indicating that dietary CLA had a potent affect on lipid transport and metabolism in vivo. Significant increases in myristic, palmitic and palmitoleic acids and a reduction in arachidonic acid were observed, suggesting an alteration in activity of delta5-, delta6- and delta9-desaturases in pig adipose tissue. In conclusion, feeding pigs diets supplemented with CLA increases carcass lipid CLA, but also results in changes in the fatty acid profile in pig fat that could potentially outweigh the benefits of CLA.     

Respiration uncoupling and metabolism in the control of energy expenditure

Metabolic energy expenditure negatively regulates energy balance. Metabolic and catabolic pathways contribute to energy expenditure. Catabolic pathways split C-containing molecules into small molecules and generate reduced coenzymes and ATP. For a given amount of substrate, any increase in energy expenditure requires either increased ATP hydrolysis or decreased ATP synthesis. In skeletal muscles substrate utilisation is coupled to ATP production, whereas ATP hydrolysis is activated during physical exercise and increases energy expenditure. In brown adipose tissue activation of cells during exposure to cold increases substrate utilisation in such a way that glucose and fatty acid oxidation detach from the orthodox coupling to ATP synthesis and result in thermogenesis. The unique mechanism of uncoupling respiration that occurs in brown adipocyte mitochondria represents an attractive strategy for promoting energy expenditure and decreasing the fat content of the body. Moreover, ectopic expression of brown fat uncoupling protein (UCP) 1 in mouse skeletal muscle and induction of UCP1 in mouse or human white adipocytes promote fatty acid oxidation and resistance to obesity. In normal conditions UCP2 and UCP3 do not seem to contribute substantially to energy expenditure. Whether the induction of UCP1, the induction of other UCP or chemical mild uncoupling represent promising strategies for attenuating nutrient efficiency and counteracting obesity should be considered.     

不同脂肪酸构成比膳食对大鼠脂联素及其受体表达的影响

目的探讨不同脂肪酸构成比膳食对大鼠脂联素及其受体表达的影响。方法将72只Wistar大鼠随机分为对照组和5个实验组(A～E),实验组分别设膳食中饱和脂肪酸(SFA)/单不饱和脂肪酸(MUFA)/多不饱和脂肪酸比值(PUFA)(S/M/P)为1:1.7:1.2、1:1:1、2:1:1、1:2:1和1:1:2,喂养12w,测定脂肪组织脂联素(adiponectin,ADPN)、骨骼肌组织脂联素受体1(AdipoR1)、肝脏组织脂联素受体2(AdipoR2)mRNA的表达水平。结果与基础组相比,1:1.7:1.2组和1:1:1组的两种脂肪组织和2:1:1组的皮下脂肪组织脂联素mRNA表达显著降低(P<0.05),其中1:1.7:1.2组下降程度较高(P<0.001)。与1:1.7:1.2组比较,其余各实验组脂联素表达水平均显著升高(P<0.05),以1:1:2组的升高程度最高(P<0.001)。各实验组AdipoR的表达水平与基础对照组并无明显差别(P>0.05)。结论高脂饮食降低脂肪组织脂联素mRNA表达水平,不饱和脂肪酸对促进脂联素基因表达和分泌有明显作用,其中PUFA的作用较MUFA显著。     

Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis

Fibroblast growth factor 21 (FGF21) was originally identified as a member of the FGF family in homology studies and is a member of the endocrine FGF subfamily that lacks heparin binding domains and is released into the circulation. A potential role as a metabolic regulator emerged when FGF21 was shown to increase glucose uptake in adipocytes. Subsequently, marked elevations in FGF21 expression were observed in mice that ate a ketogenic diet and when fasting, which suggests that FGF21 expression plays a role in the adaptation to metabolic states that require increased fatty acid oxidation. Consistent with this evidence, FGF21 knockout mice were not able to respond appropriately to consumption of a ketogenic diet. FGF21 expression is downstream of peroxisome proliferator-activated receptor (PPAR) α in the liver and PPARγ in adipose tissue. FGF21 concentrations are higher in both rodent and human obesity, and recent data suggest that obesity may be an FGF21-resistant state. Recent data increasingly suggest that FGF21 is an important metabolic regulator that may have potential clinical implications.     

Naringin reduces fat deposition by promoting the expression of lipolysis and β-oxidation related genes

AimsNaringin, a flavonoid present in citrus fruits, has been known for the capacity to reduce lipid synthesis and anti-inflammatory. In this study, we investigated whether naringin increases lipolysis and fatty acid β-oxidation to change fat deposition.MethodsIn in vivo experiment, obese adult mice (20-weeks-old, n = 18) were divided into control group fed with normal diet and naringin-treated group fed with naringin-supplemented diet (5 g/kg) for 60 days, respectively. In in vitro experiment, differentiated 3T3-L1 adipocytes were treated for four days with or without naringin (100 µg/mL).ResultsSupplementing naringin significantly reduced the body weight, abdominal fat weight, blood total cholesterol content of mice, but did not affect food intake. In addition, naringin decreased levels of pro-inflammatory factors in adipose tissue including interleukin-1β (IL-1β), interleukin-6 (IL-6), and monocyte chemotactic protein 1 (MCP-1). Naringin increased the expression of AMP-activated protein kinase (AMPK), a key factor in cellular energy metabolism, and raised the ratio of p-AMPK/AMPK in mouse liver tissue. The protein expression of hormone-sensitive lipase (HSL), phospho-HSL563 (p-HSL563), p-HSL563/HSL, and adipocyte triglyceride lipase (ATGL) was significantly increased in the adipose tissue of naringin-treated mice. Furthermore, naringin enhanced the expression of fatty acid β-oxidation genes, including carnitine palmitoyl transferase 1 (CPT1), uncoupling protein 2 (UCP2), and acyl-coenzyme A oxidase 1 (AOX1) in mouse adipose tissue. In in vitro experiment, similar findings were observed in differentiated 3T3-L1 adipocytes with naringin treatment. The treatment remarkably reduced intracellular lipid content, increased the number of mitochondria and promoted the gene expression of HSL, ATGL, CPT1, AOX1, and UCP2 and the phosphorylation of HSL protein.ConclusionNaringin reduced body fat in obese mice and lipid content in differentiated 3T3-L1 adipocytes, which was associated with enhanced AMPK activation and upregulation of the expression of the lipolytic genes HSL, ATGL, and β-oxidation genes CPT1, AOX1, and UCP2.