二氢杨梅素经激活SIRT1-AMPK通路抑制高脂饮食诱导的肥胖小鼠肝脏脂质沉积

目的探究二氢杨梅素(dihydromyricetin,DHM)对高脂饮食诱导的肥胖小鼠肝脏脂质蓄积的作用及其机制。方法C57BL/6J小鼠60只,随机分为6组(n=10):①ND组:正常饲料;②ND+L-DHM组:正常饲料+低剂量DHM(125 mg·kg^-1·d^-1);③ND+H-DHM组:正常饲料+高剂量DHM(250 mg·kg^-1·d^-1);④HFD组:高脂饲料;⑤HFD+L-DHM组:高脂饲料+低剂量DHM;⑥HFD+H-DHM组:高脂饲料+高剂量DHM。记录小鼠体重;16周后,测空腹血脂;计算体脂重量;肝脏HE和油红O染色;荧光定量PCR和Western blot检测肝脏SIRT1、AMPK、ACC、FAS、SREBP-1和PPARα、CPT1的表达。结果与ND组相比,HFD组小鼠体重、体脂、血清TG、TC、HDL水平明显增加;肝脏内脂肪蓄积增加,肝脏SREBP-1c、FAS、ACC1表达增加,而PPARα、CPT1、SIRT1和AMPK表达下降。经DHM处理后,HFD小鼠上述指标发生逆转;但ND小鼠上述指标无明显改变。结论DHM可能通过激活SIRT1-AMPK通路抑制脂质合成,促进脂质分解,改善高脂饮食诱导的肥胖小鼠肝脏脂质沉积。     

Effect of oxymatrine on lipid metabolism regulated genes in liver of fat-induced insulin resistance in ApoE-/-mice北大核心CSCD

Aim To investigate the effect of oxymatrine on lipid metabolism regulated genes in liver in fat-induced insulin resistance in ApoE-/- mice. Methods Seventeen C57BL/6J male mice were selected in normal control group. Sixty-eight ApoE-/- mice with high fat diet for 16 weeks, were randomly divided into model group, oxymatrine low, middle and high dose groups. Then they were gavaged for 8 weeks. Body weight and general biochemical indicators were determined in mice. The mRNA and protein expression levels of LPL, FAT/CD36, CPT1, UCP2, SREBP-1 c, FAS and ACC were examined by real-time PCR and Western blot in the liver. Results Compared with model group, oxymatrine reduced body weight (BW) , fasting blood glucose (FBG), cholesterol (TC) , triglyceride (TG) , free fatty acids (FFA), fasting plasma insulin (FINS) and insulin resistance index(HOMA-IR) (P < 0. 05) , while improved glucose infusion rate (GIR) . Oxymatrine down-regulated the mRNA and protein expression of LPL, FAT/CD36, UCP2, SREBP-1c, FAS and ACC(P <0. 05) ,and up-regulated the mRNA and protein expression of CPT1 in varying degrees (P < 0. 05). Conclusion Oxymatrine can regulate the expression of lipid metabolism regulated genes in liver and improve insulin resistance in ApoE-/- mice induced by high fat diet.     

五味子-甘草配伍的调血脂作用及对甘油三酯合成途径的影响

目的探讨五味子及配伍甘草对正常小鼠血脂及对肝脏TG合成途径的影响。方法ICR♂小鼠,按体重随机分为4组,即对照组(C)、五味子组(SF)、五味子-甘草(SG)1∶1和1∶1.5组。C组灌胃生理盐水,SF、SG 1∶1和1∶1.5组分别灌胃含五味子生药量为3.9 g·kg^-1的提取物,共计10 d。生化法检测血清TG、TC、LDL-C、HDL-C水平及ALT活性;ELISA检测肝脏FAS、ACC活性和GPAT、ACO水平,免疫组化法检测肝脏SREBP-1c和PPARα蛋白表达。结果与C组比,SF明显升高血清TG和TC水平,降低HDL水平,病理学可见较多脂肪空泡,少量炎性细胞浸润,升高ACC活性和GPAT水平,上调肝脏SREBP-1c的表达,下调PPARα的表达。与SF相比,SG 1∶1明显降低血清TG水平及ALT活性,降低GPAT和ACO水平;SG 1∶1和1∶1.5下调肝脏SREBP-1c的表达,上调PPARα的表达。结论大剂量五味子可升高正常小鼠血清TG和TC,配伍甘草可调节TG合成途径相关蛋白而改善升高的血脂。     

Inhibition of stearoyl-CoA desaturase1 activates AMPK and exhibits beneficial lipid metabolic effects in vitro

Stearoyl-CoA desaturase1 (SCD1) whole body deficiency protects mice from diet-induced obesity. However the specific mechanism of how SCD1 deficiency protects mice from obesity is not clear yet. To understand the tissue-specific role of SCD1 in energy homeostasis, we investigated the responses of adipocytes, hepatocytes and myotubes to SCD1 inhibition. 3T3-L1 adipocytes treated with a SCD1 inhibitor had decreased expression of lipogenic genes including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and sterol-regulatory element binding protein 1c (SREBP1c) while the expression of fatty acid oxidative genes including carnitine palmitoyltransferase 1 (CPT1), uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α) remained unaltered. In mouse primary hepatocytes, treatment with the inhibitor reduced the expression of FAS, ACC, and SREBP1c but increased the expression of fatty acid oxidative genes including acyl-CoA oxidase (AOX), CPT1, and PGC1-α. In addition, inhibitor-treated C2C12 myotubes showed decrease in ACC and FAS expression and increase in expression of CPT1, AOX and PGC1-α. AMP-activated protein kinase (AMPK) is known to regulate cellular metabolism in response to available energy and AMPK activation is associated with enhancement of fatty acid oxidation and suppression of lipogenesis. In all tested cell models, AMPK phosphorylation was increased significantly when SCD1 was inhibited. Taken together, our results indicate that inhibition of SCD1 activity has beneficial lipid metabolic effects of decreased lipogenesis and/or increased fatty acid oxidation, which is at least in part due to an increase of AMPK activation.     

人参皂苷Compound K通过AMPK及SREBP1途径改善非酒精性脂肪肝的机制研究

目的：研究人参皂苷Compound K（CK）对非酒精性脂肪肝的改善作用及其与腺苷酸激活蛋白激酶（AMPK）及固醇调节元件结合蛋白（SREBP1）信号转导通路的关系。方法：采用高脂饲料喂养C57BL/6J雄性小鼠9周,建立非酒精性脂肪肝动物模型;9周后随机分为5组,正常饲料组（RD）,高脂饲料组（HFD）,给药组（HFD+CK 3,9,27 mg·kg^-1）,每天灌胃给药1次,每周测2次体质量,连续11周。实验结束后,分别称量小鼠体质量和肝质量;检测三酰甘油（TG）、胆固醇（cholesterol）、非游离脂肪酸（NEFA）、谷草转氨酶（AST）和谷丙转氨酶（ALT）水平。苏木素-伊红（HE）染色观察肝脏病理变化,Western blot法检测AMPK和乙酰辅酶A羧化酶（ACC）的磷酸化表达,PCR法检测脂肪合成转录因子SREBP1及其靶基因（FAS、SCD1）的基因表达。结果：治疗11周后,与RD组比较, HFD组小鼠肝质量及肝质量与体质量的比值显著增加（P<0.001,P<0.05）,HE染色显示HFD组较RD组肝细胞明显增大且伴有大泡性脂肪变,说明高脂饲料诱导非酒精性脂肪肝模型的建立。与HFD组比较,给药组小鼠体质量、肝质量显著降低（P<0.05）,血脂（TG、CHO、NEFA）和肝功（sAST和sALT）指标也显著降低（P<0.05,P<0.01,P<0.001）;HE染色也说明给药组能够明显改善肝脏病理状态,从而改善肝细胞脂肪变性;Western blot结果显示HFD组较RD组,AMPK和ACC磷酸化均被抑制,给药组较HFD组,AMPK和ACC均被磷酸化,且随药物浓度的增加,磷酸化越明显;PCR法结果显示HFD较RD组,脂肪合成转录因子SREBP1及其靶基因表达显著增强,而在给药组上述基因表达均显著被抑制。结论：CK对非酒精性脂肪肝具有改善作用,其机制之一可能是通过激活AMPK和ACC的磷酸化、抑制脂肪合成转录因子SREBP1及其靶基因的表达来实现的。     

Ferulic acid improves lipid and glucose homeostasis in high‐fat diet‐induced obese mice

Ferulic acid (FA) is a plant phenolic acid that has several pharmacological effects including antihyperglycaemic activity. Thus, the objective of this study is to investigate the effect of FA on glucose and lipid metabolism in high‐fat diet (HFD)‐induced obese mice. Institute for Cancer Research (ICR) mice were fed a HFD (45 kcal% fat) for 16 weeks. At the ninth week of induction, the obese mice were orally administered with daily FA doses of 25 and 50 mg/kg for the next eight weeks. The results show that FA significantly reduced the elevated blood glucose and serum leptin levels, lowered the insulin resistance, and increased the serum adiponectin level. Moreover, serum lipid level, and liver cholesterol and triglyceride accumulations were also reduced. The histological examination showed clear evidence of a decrease in the lipid droplets in liver tissues and smaller size of fat cells in the adipose tissue in the obese mice treated with FA. Interestingly, FA reduced the expression of hepatic lipogenic genes such as sterol regulatory element‐binding protein 1c (SREBP1c), fatty acid synthase (FAS), and acetyl‐CoA carboxylase (ACC). It could also up‐regulate hepatic carnitine palmitoyltransferase 1a (CPT1a) gene and peroxisome proliferator‐activated receptor alpha (PPARα) proteins. The FA treatment was also found to suppress the protein expressions of hepatic gluconeogenic enzymes, phosphoenolpyruvate carboxylase (PEPCK) and glucose‐6‐phosphatase (G6Pase). In conclusion, the findings of this study demonstrate that FA improves the glucose and lipid homeostasis in HFD‐induced obese mice probably via modulating the expression of lipogenic and gluconeogenic genes in liver tissues.     

Effect and mechanism of waterborne prolonged Zn exposure influencing hepatic lipid metabolism in javelin goby Synechogobius hasta

The present study was conducted to determine the effect and mechanism of waterborne Zn exposure influencing hepatic lipid deposition and metabolism in javelin goby Synechogobius hasta. S. hasta were exposed to four waterborne Zn concentrations (Zn 0.005 [control], 0.18, 0.36 and 0.55 mg l^?1, respectively) for 60 days. Sampling occurred at days 20, 40 and 60, respectively. Zn exposure increased Zn content, declined hepatic lipid content and reduced viscerosomatic and hepatosomatic indices and lipogenic enzyme activities, including 6‐phosphogluconate dehydrogenase (6PGD), glucose‐6‐phosphate dehydrogenase (G6PD), malic enzyme (ME) and fatty acid synthase (FAS). At days 20 and 60, Zn exposure decreased hepatic mRNA levels of 6PGD, G6PD, ME, FAS, acetyl‐CoA carboxylase (ACC)α, ACCβ, hormone‐sensitive lipase (HSL)a, HSLb, sterol‐regulator element‐binding protein (SREBP)‐1, peroxisome proliferators‐activated receptor (PPAR)α and PPARγ. However, the mRNA levels of CPT 1 and adipose triglyceride lipase increased following Zn exposure. On day 40, Zn exposure reduced hepatic mRNA expression of 6PGD, G6PD, ME, FAS, ACCα, ACCβ, HSLa, HSLb, SREBP‐1 and PPARγ but increased mRNA expression of CPT 1, adipose triglyceride lipase and PPARα. General speaking, Zn exposure reduced hepatic lipid content by inhibiting lipogenesis and stimulating lipolysis. For the first time, the present study provided evidence that chronic Zn exposure differentially influenced mRNA expression and activities of genes and enzymes involved in lipogenic and lipolytic metabolism in a duration‐dependent manner, and provided new insight into the relationship between metal elements and lipid metabolism. Copyright © 2015 John Wiley & Sons, Ltd.     

Taurine prevents high‐fat diet‐induced‐hepatic steatosis in rats by direct inhibition of hepatic sterol regulatory element‐binding proteins and activation of AMPK

This study investigated if the protective effect of taurine against high fat diet‐induced hepatic steatosis involves modulating the hepatic activity of 5' AMP‐activated protein kinase (AMPK) and levels/activity of the sterol regulatory element‐binding proteins‐1/2 (SREBP1/2). Rats were divided into four groups (n = 12/group) as (a) STD, fed standard diet (3.85 kcal/g); (b) STD + taurine (500 mg/kg); (c) HFD, fed HFD (4.73 kcal/g); and (d) HFD + taurine. All treatments were conducted for 12 weeks. Independent of food intake or modulating glucose or insulin levels, taurine administration to STD and HFD‐fed rats significantly lowered weekly weight gain and the accumulation of the retroperitoneal, visceral and subcutaneous fats. In both groups, taurine also reduced serum and hepatic levels of triglycerides and cholesterol and reduced hepatic mRNA and protein levels of fatty acid synthase (FAS), acetyl CoA carboxylase‐1 (ACC‐1), HMG‐CoA‐reductase and HMG‐CoA synthetase. In control rats only, taurine reduced hepatic levels of mature forms of sterol regulatory element‐binding proteins (SREBP)‐1/2. In HFD‐fed rats, taurine reduced SREBP‐1/2 precursor and mature forms in the livers of HFD‐fed rats. Besides, taurine significantly increased levels of glutathione (GSH), the activity of superoxide dismutase (SOD), and the activity of AMPK and its downstream β‐oxidation genes including peroxisome proliferator‐activated receptor‐α (PPAR‐α) and carnitine palmitoyltransferase (CPT‐1) in the livers of both the control and HFD‐fed rats. In conclusion, taurine protects against HFD‐induced hepatic steatosis stimulating antioxidant levels, and concomitant stimulating hepatic β‐oxidation and suppressing lipid synthesis, mediated by activation of AMPK and suppression of SREBP‐1.     

Alleviative effect of ciliary neurotrophic factor analogue on high fat‐induced hepatic steatosis is partially independent of the central regulation

Ciliary neurotrophic factor (CNTF) analogues were reported to ameliorate fatty liver in db/db or high‐fat diet‐fed mice. It is generally thought that CNTF exerts its actions centrally. The aim of this study was to investigate whether peripheral effects of CNTF analogues are involved in the therapeutic effect on high fat‐induced hepatic steatosis. The rat model of fatty liver was induced by a high‐fat diet (HFD) for 12 weeks. In the next 2 weeks, rats were fed the HFD along with subcutaneous injection of vehicle or mutant recombinant human CNTF (rhmCNTF 0.05‐0.2 mg/kg per day). Steatotic HepG2 cells were induced by 50% fetal bovine serum (FBS) for 48 hours, and then treated with rhmCNTF for 24 hours. The results showed that after rhmCNTF treatment, hepatic triglyceride (TG) accumulation was attenuated both in vivo and in vitro. RhmCNTF increased protein expression of CPT‐1 and PPARα, and decreased SREBP‐1c, FAS and SCD‐1 in steatotic HepG2 cells. But the production of nitric oxide and 8‐isoPGF_2α in steatotic HepG2 cells was not affected by rhmCNTF. These results suggest that rhmCNTF has a peripheral effect that alleviates fat‐induced hepatic steatosis.     

Osthol ameliorates fat milk-induced fatty liver in mice by regulation of hepatic sterol regulatory element-binding protein-1c/2-mediated target gene expression

The objective of this study was to examine the therapeutic effect of osthol, an active constituent of Cnidium monnieri (L.) Cusson (Apiaceae), in hyperlipidemic fatty liver mice and investigate the potential mechanism of the osthol treatment. A mouse model with hyperlipidemic fatty liver was induced by orally feeding the fat milk for 4 weeks. The experimental mice were then treated with osthol 10-40 mg/kg for 6 weeks. After oral administration, the mice in the model and medicine-treated groups were continuously given the fat milk for 2 weeks again. Whereafter, the lipid levels in serum and liver, hepatic weight coefficient and histopathological evaluation were measured. The sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, fatty acid synthase (FAS), low density lipoprotein (LDL) receptor and cholesterol 7α-hydroxylase (CYP7A) mRNA expressions in liver were examined. The results showed that in the osthol-treated groups, the total cholesterol, triglyceride and free fatty acid levels in serum and liver, and the hepatic weight coefficient were gradually decreased with dose. Importantly, the histopathological evaluation of liver specimens demonstrated that osthol might decrease lipid accumulation. Osthol could increase the mRNA expression of CYP7A and decrease the mRNA expressions of SREBP-1c, SREBP-2, FAS and LDL receptor in liver in fat milk-induced fatty liver mice. These results suggested that osthol might exert the therapeutic effect on fat milk-induced fatty liver in mice, by inhibiting hepatic SREBP-1c/2 mRNA expressions and subsequent modulation of SREBP-1c/2-mediated target genes such as FAS, CYP7A and LDL receptor.     

Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice

Sirtuin 1 (SIRT1) is a mammalian NAD⁺-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-κB), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.     

益肾排毒丸调节AMPK/ACC信号通路对db/db小鼠肝损伤的保护作用研究

目的：探究益肾排毒丸（YSPDW）对db/db小鼠肝损伤的保护作用及其对脂代谢通路的影响机制。方法：C57BL/6小鼠作为空白对照组、8周龄的db/db小鼠分为非酒精性脂肪肝（non-alcoholic fatty liver disease,NAFLD）模型组、益肾排毒丸治疗组和二甲双胍阳性对照组。给药8周后检测小鼠肝脏系数、随机血糖、肝功能（丙氨转氨酶ALT、谷草转氨酶AST）、血脂（总胆固醇TC、三酰甘油TG、高密度脂蛋白胆固醇HDL-C、低密度脂蛋白胆固醇LDL-C）、肝脏脂质（TC、TG）、肝脏抗氧化因子（谷胱甘肽过氧化物酶GSH-Px、谷胱甘肽GSH、超氧化物歧化酶SOD、丙二醛MDA、过氧化氢酶CAT）、肝脏炎性因子（TNF-α、IL-6、IL-1β、MCP-1）等指标的变化。HE和PAS染色评估小鼠肝脏形态变化、脂肪变性和糖原沉积。Western blot检测脂代谢AMPK/ACC信号通路相关蛋白表达。结果：与模型组相比,益肾排毒丸给药组和二甲双胍组小鼠随机血糖和肝脏系数显著降低。生化指标检测结果显示益肾排毒丸可显著降低NAFLD模型小鼠血清AST、ALT、TC、TG水平和肝组织TC、TG、MDA水平,升高HDL-C含量,发挥肝保护作用;ELISA结果表明益肾排毒丸能明显升高NAFLD小鼠肝组织GSH-Px、GSH和SOD活性,显著降低肝脏炎性细胞因子TNF-α、IL-6、IL-1β和MCP-1的水平,表明益肾排毒丸可增加机体抗氧化能力,抑制炎症因子释放。HE和PAS结果显示益肾排毒丸可明显减轻肝组织脂肪变性和炎症细胞浸润,改善肝细胞的结构和形态完整。Western blot结果表明,益肾排毒丸能激活AMPK/ACC信号通路,显著增加模型小鼠肝脏p-AMPK和p-ACC蛋白表达。结论：益肾排毒丸可能通过促进AMPK/ACC信号通路来改善肝脏氧化应激、炎性反应,减少脂质合成,从而改善NAFLD的肝损伤。     

Studies on the mechanism of SIRT1/AMPK signaling pathway between hepatocytes and hepatic stellate cells

OBJECTIVE To investigate the mechanism of SIRT1/AMPK signaling pathway between hepatocytes and hepatic stellate cells(HSCs).METHODS Normal human Chang liver cells and human hepatic stellate cell line,LX-2 cells were treated with SRT1720(10μmol·L~(-1))and AICAR(500μmol·L~(-1))prior to ethanol(50 mmol·L~(-1)) for 24 and 48 h.Cell viability was analyzed by methyl thiazolyl tetrazolium assay.SIRT1,AMPK and p-AMPK m RNA levels for 24 h and 48 h were analyzed by RT-PCR,SIRT1,AMPK and p-AMPK protein expressions in the supernatant at 24 and 48 h was detected by Western blot.RESULTS SRT1720 and AICAR effectively decreased LX-2 cell viabilities and exhibited scarcely little toxicity in human Chang liver cells.SRT1720 and AICAR attenuated collagen-I,α-smooth muscle actin(α-SMA)levels,activated liver kinase B-1(LKB1)and AMPK phosphorylation in ethanol treated LX-2 cells.Meanwhile,SRT1720 and AICAR enhanced SIRT1 expression mediated by ethanol both in Chang liver cells and LX-2 cells.Furthermore,SRT1720 and AICAR suppressed the expression of sterol regulatory element-binding protein-1(SREBP-1)to regulate fatty acid synthesis.CONCLUSION SIRT1 agonist and AMPK agonist blocked the crosstalk between hepatocytes and HSCs via SIRT1/AMPK signaling pathway to modulate hepatocytes accumulation of lipid and HSCs activation.     

蛇床子素通过激活过氧化物酶体增殖物激活受体α调节肝细胞内脂肪酸代谢

目的探讨蛇床子素是否通过激活过氧化物酶体增殖物激活受体(PPAR)α调节肝细胞内的脂肪酸代谢。方法 大鼠肝细胞在用蛇床子素12.5～100μmol.L-1作用24 h后,用比色法测定细胞内甘油三酯(TG)和游离脂肪酸(FFA)含量,用逆转录聚合酶链反应法测定PPARαmRNA表达的变化。PPARα抑制剂MK886 1μmo.lL-1预处理肝细胞2 h后,观察蛇床子素100μmo.lL-1作用24 h后对细胞内TG和FFA含量以及PPARα调控的靶基因包括固醇调节元件结合蛋白(SREBP)-1/2、脂肪酸合酶(FAS)、二脂酰甘油酰基转移酶(DGAT)、肉碱软脂酰转移酶(CPT)-1a、脂肪酸转运蛋白(FATP)4和肝脂肪酸结合蛋白(L-FABP)mRNA表达的影响。结果 蛇床子素12.5～100μmol.L-1可明显降低肝细胞内TG和FFA的含量(P<0.01),同时也能明显增加肝细胞内PPARαmRNA的表达(P<0.01)。在用PPARα抑制剂MK886预处理后,蛇床子素降低肝细胞内TG和FFA的作用则明显被减弱(P<0.01),同时抑制SREBP-1/2,FAS和DGAT mRNA表达的作用明显减弱或完全消失(P<0.01),增加CPT-1a,FATP4和L-FABPmRNA表达的作用也明显减弱或完全消失(P<0.01)。结论 蛇床子素通过激活肝细胞中PPARα后可降低细胞中的TG和FFA含量,其机制与激活PPARα后随后抑制SREBP-1/2,FAS和DGAT的基因表达以及增加CPT-1a,FATP4和L-FABP的基因表达有关。     

Resveratrol exerts anti-obesity effects via mechanisms involving down-regulation of adipogenic and inflammatory processes in mice

Resveratrol is a natural polyphenolic stilbene derivative found in a variety of edible fruits, including nuts, berries, and grape skin. Although resveratrol has been suggested to improve thermogenesis in the brown adipose tissues of obese animals, there have been no reports on the anti-adipogenic and anti-inflammatory effects of resveratrol in the white adipose tissues of obese animals. The primary aim of this study was to investigate whether resveratrol attenuates high-fat diet (HFD)-induced adipogenesis and inflammation in the epididymal fat tissues of mice and to explore the underlying mechanisms involved in this attenuation. In comparison with HFD-fed mice, mice fed with a 0.4% resveratrol-supplemented diet (RSD) showed significantly lower body weight gain (−48%), visceral fat-pad weights (−58%), and plasma levels of triglyceride, FFA, total cholesterol, glucose, tumor necrosis factor (TNF) α, and monocyte chemoattractant protein-1 (MCP1). Resveratrol significantly reversed the HFD-induced up-regulation of galanin-mediated signaling molecules (GalR1/2, PKCδ, Cyc-D, E2F1, and p-ERK) and key adipogenic genes (PPARγ2, C/EBPα, SREBP-1c, FAS, LPL, aP2, and leptin) in the epididymal adipose tissues of mice. Furthermore, resveratrol significantly attenuated the HFD-induced up-regulation of pro-inflammatory cytokines (TNFα, IFNα, IFNβ, and IL-6) and their upstream signaling molecules (TLR2/4, MyD88, Tirap, TRIF, TRAF6, IRF5, p-IRF3, and NF-κB) in the adipose tissues of mice. The results of this study suggest that resveratrol inhibits visceral adipogenesis by suppressing the galanin-mediated adipogenesis signaling cascade. It may also attenuate cytokine production in the adipose tissue by repressing the TLR2- and TLR4-mediated pro-inflammatory signaling cascades in HFD-fed mice.     

基于PPARs信号通路探索CB1对脂质代谢的调节作用

目的 研究CB1对PPARs信号通路在高脂饮食诱导肥胖小鼠脂质代谢的调节作用.方法 构建小鼠肥胖模型,观察给予CB1抑制剂利莫那班后小鼠体重、肝脏重量及血清生化指标的变化,并检测CB1、PPARα、PPAR β和PPARγ基因在各组织mRNA水平的表达情况.结果 利莫那班降低了小鼠的体重和肝脏重量(P＜ 0.05);改善了血清生化指标(P＜0.05);各组织中CB1基因mRNA水平的表达降低(P＜ 0.05);PPARα、PPARγ基因在皮下脂肪、内脏脂肪、肝脏组织mRNA水平的表达显著增高(P＜ 0.05);PPAR 3基因在各组织mRNA水平表达情况差异无统计学意义.结论 CB1通过作用于PPARα、PPARγ调节脂质代谢,为临床上脂质代谢紊乱的治疗提供了另一个可靠的理论依据.     

Synthesis of a new [6]-gingerol analogue and its protective effect with respect to the development of metabolic syndrome in mice fed a high-fat diet

To determine the effects of a [6]-gingerol analogue (6G), a major chemical component of the ginger rhizome, and its stable analogue after digestion in simulated gastric fluid, aza-[6]-gingerol (A6G), on diet-induced body fat accumulation, we synthesized 6G and A6G. Mice were fed either a control regular rodent chow, a high-fat diet (HFD), or a HFD supplemented with 6G and A6G. Magnetic resonance imaging adiposity parameters of the 6G- and A6G-treated mice were compared with those of control mice. Supplementation with 6G and A6G significantly reduced body weight gain, fat accumulation, and circulating levels of insulin and leptin. The mRNA levels of sterol regulatory element-binding protein 1c (SREBP-1c) and acetyl-CoA carboxylase 1 in the liver were significantly lower in mice fed A6G than in HFD control mice. Our findings indicate that A6G, rather than 6G, enhances energy metabolism and reduces the extent of lipogenesis by downregulating SREBP-1c and its related molecules, which leads to the suppression of body fat accumulation.