PPARα在肝脏相关疾病中作用的研究进展

过氧化物酶体增殖物激活受体α(perixisome proliferation-activated receptor alpha,PPARα)是核受体超家族成员,是参与肝脏β氧化的主要调控蛋白,通过诱导下游靶基因转录,从而发挥其重要的生物学功能。近年来,肝脏相关疾病的研究备受关注,肝癌(主要以肝细胞性肝癌为主)也呈年轻化趋势。PPARα的活化能够降低高脂喂养小鼠肝脏中甘油三酯的含量或脂肪的生成量。此外,PPARα通过调控细胞增殖与凋亡进程等多种机制参与肝癌进程。现综述PPARα在非酒精性脂肪肝、酒精性脂肪肝和肝细胞性肝癌进程中的作用。     

Cidea和Cidec促进肝脏中脂类的积累

目的:探讨Cidea和Cidec对肝脏中脂滴大小和脂类积累的影响。方法:首先,检测ob/ob肥胖小鼠的脂肪肝中Cidea和Cidec的表达情况。然后,采用腺病毒系统在野生型小鼠肝脏中过表达Cidea和Cidec,以及在ob/ob小鼠肝脏中基因沉默Cidea和Cidec,检测肝脏中脂滴大小和脂积累情况。结果:Cidea和Cidec在脂肪性肝脏中高表达。肝脏细胞中过表达Cidea和Cidec促进大脂滴的形成并能促进小鼠肝脏中的脂积累,且二者有协同作用。在脂肪肝中沉默Cidea和Cidec能缓解脂肪肝的程度,且脂合成基因的下调,线粒体活性增加。Cidea和Cidec的共沉默能进一步降低肝脏中的脂类积累。结论:Cidea和Cidec在促进肝脏的脂积累中起重要作用,并且二者有协同作用。     

激活PPARα缓解PPARγ诱导的小鼠脂肪肝

目的研究PPARα激活后对PPARγ诱导小鼠脂肪肝的影响。方法以4~5周龄C57BL/6J小鼠为模型,实验分为4组:正常饮食组;0.125%Wy-14,643处理组;PPARγ腺病毒(Ad/PPARγ)注射组;先给予0.125%Wy-14,643饮食再注射Ad/PPARγ组。实验结束时,收集肝脏组织称重、照相,HE、油红O染色观察PPARα激活后对PPARγ诱导肝脏脂肪变性的影响。结果野生型小鼠给予PPARα激动剂Wy-14,643处理8 d,与对照组相比,处理组小鼠肝脏明显增大,呈现过氧化物酶体增殖反应;野生型小鼠给予Ad/PPARγ5 d,小鼠肝脏显著增大,出现脂肪肝;给予PPARα激动剂Wy-14,643 3 d,再给予Ad/PPARγ5 d,小鼠肝脏增大更加显著,HE染色、油红O染色结果显示小鼠肝脏脂肪变性明显减轻。结论激活PPARα能够缓解PPARγ诱导的小鼠肝脏脂肪变,为脂肪肝的预防和治疗提供了新的研究思路和靶点。     

猪骨胶原蛋白肽缓解高脂饮食诱导小鼠肝脏氧化应激的基因芯片分析

本研究探讨猪骨胶原蛋白肽降血脂作用和抑制高脂饮食诱导肝脏抗氧化应激的作用机理。40只小鼠分为5组,分别饲喂6 w正常日粮、高脂日粮、添加1.6%钙的高脂日粮、添加1%胶原蛋白肽的高脂日粮和添加1.6%钙+1%胶原蛋白肽的高脂日粮。研究发现:与正常组相比,高脂日粮小鼠血脂和体重明显升高。1.6%钙处理可抑制体重过度升高,1%胶原蛋白肽和高钙可协同抑制调节血脂,防止体重升高。高脂主要通过影响肝脏生理节律和过氧化物酶体增生物激活受体信号通路引起脂代谢异常,高钙和骨胶原蛋白肽可显著抑制肝脏氧化应激,抑制生理节律紊乱。     

lepr和mc4r基因突变斑马鱼的制备及表型分析

肥胖已经成为全球性的公共卫生问题,严重影响人类的身体健康和生活品质。本文运用CRISPR/Cas9技术,构建了肥胖相关基因——瘦素受体(leptin receptor,lepr)和黑素皮质素受体4(melanocortin-4 receptor,mc4r)的斑马鱼突变体,并对其进行形态和功能分析。结果显示,lepr~(-/-)和mc4r~(-/-)斑马鱼在胚胎和幼鱼期没有明显异常,但在成年期,lepr~(-/-)和mc4r~(-/-)斑马鱼相比对照进食增多、体重增加、体脂含量升高,呈现肥胖表型。血糖测定结果显示,饱食喂养条件可以诱导lepr~(-/-)和mc4r~(-/-)成年斑马鱼出现糖耐量受损的现象。进一步地,运用real time RT-PCR对76个能量代谢相关基因在lepr~(-/-)和mc4r~(-/-)斑马鱼肝脏中转录表达水平进行检测,并与Lep~(ob/ob)小鼠肝脏c DNA microarray的数据比较,发现胰岛素/胰岛素样生长因子信号转导通路(insulin/IGF signaling pathway,ISS)相关的基因在lepr~(-/-)斑马鱼和Lep~(ob/ob)小鼠肝脏中表达变化具有较高的正相关性,提示肥胖调控网络在进化中维持了一定的功能保守性。     

生酮饮食通过上调肝脏和棕色脂肪组织PPARα提高小鼠耐低温能力

本文旨在探究短期生酮饮食对小鼠耐低温能力的影响及过氧化物酶体增殖物激活受体α (peroxisome proliferatoractivated receptor α, PPARα)在其中的作用及机制。将C57BL/6J小鼠分为正常饮食(WT+ND)组与生酮饮食(WT+KD)组,室温下分别用正常或生酮饮食饲料喂养2 d后,将其置于4°C环境中12 h,检测小鼠在低温条件下核心温度、血糖、血压的变化,并用Western blot检测PPARα和线粒体解偶联蛋白1 (uncoupling protein 1, UCP1)蛋白表达水平。将PPARα敲除小鼠分为正常饮食(PPARα^-/-+ND)组与生酮饮食(PPARα^-/-+KD)组,室温下分别用正常或生酮饮食饲料喂养2 d后,将其置于4°C环境中12 h,同样进行上述指标检测。结果显示,在室温下,与WT+ND组相比,WT+KD组小鼠肝脏及棕色脂肪组织中PPARα和UCP1蛋白水平均显著上调。在低温条件下,与WT+ND相比,WT+KD组小鼠核心温度及血糖升高,平均动脉压降低;生酮饮食可上调WT+KD...     

敲除Nrf2促进高脂饮食诱导小鼠肝脏NF-kB的活化

目的：氧化应激和炎症反应是NASH进展的关键因素,同时二者之间存在着密切关系,而转录因子Nrf2和NF-kB分别是氧化应激和炎症信号通路的关键调控靶点,因此,研究Nrf2对高脂饮食诱导小鼠肝脏NF-kB信号通路的影响,对探讨NASH进展具有重要的意义。方法：雄性野生型（WT）和Nrf2基因敲除（Nrf2-/-）ICR小鼠各10只,随机分为WT对照组（Control）、Nrf2-/-对照组（KO）、WT高脂饮食组（HFD）和Nrf2-/-高脂饮食组（KOHFD）（n=5）。喂养8周后,观察肝脏光镜下改变,检测肝脏GSH、MDA、TNFα和IL-6水平。Western-Blot检测肝脏NF-kB蛋白表达水平,观察敲除Nrf2对肝脏NF-kB活性作用的影响。结果：1.光镜下观察,Control组与KO组小鼠肝脏结构无明显变化,HFD组小鼠肝脏呈现大片脂肪沉积和炎症细胞浸润,KOHFD组小鼠肝脏则呈现明显的大泡性变性,且炎症细胞浸润较HFD组明显加重;2.与Control组相比,KO组小鼠肝脏MDA轻度升高,GSH轻度降低,但无明显差异,而HFD组和KOHFD组小鼠肝脏MDA显著升高（P〈0.05）,GSH显著降低（P〈0.05）,且KOHFD组MDA明显高于HFD组（P〈0.05）,GSH明显低于HFD组（P〈0.05）。3.ELISA结果显示,与Control组相比,KO组小鼠肝脏TNFα和IL-6分泌轻度增加,而HFD组和KOHFD组小鼠肝脏TNFα与IL-6水平显著升高（P〈0.05）,且KOHFD组小鼠肝脏TNFα与IL-6显著高于HFD组（P〈0.05）;4.Western-Blot结果显示,Control组和KO组之间无明显差异,而KOHFD组和HFD组小鼠肝脏胞核NF-kB蛋白表达水平显著升高,且KOHFD组高于HFD组。结论：敲除Nrf2可以显著加重高脂饮食诱导的小鼠肝脏氧化应激水平,进而促进NF-kB的活化,从而为通过以Nrf2为靶点治疗NASH提供重要的实验依据。     

不同游泳运动对小鼠酒精性脂肪肝形成的改善作用*

目的: 探讨7周不同负荷游泳运动对酒精性脂肪肝小鼠肝脏脂质代谢的改善作用及微RNA-34a(miR-34a)与过氧化物酶体增殖物激活的受体α(PPARα)的调控关系。方法: 50只雄性KM小鼠,随机分成空白组(K,n=10)和酒精性脂肪肝组(AFLD,n=40),AFLD组通过50%乙醇的谷酒王0.2 ml/10 g WT灌服7周,每周休息1 d。成功构模后,分成模型组(M)、30 min游泳运动组(LE)、60 min游泳运动组(ME)、90 min负重游泳运动组(HE,尾部铅皮负重体重的5%),每组10只,每周干预6 d,共7周。结束后,提取血清和肝脏组织,测定小鼠肝脏指数、内脏脂肪比,肝细胞损伤指标谷丙转氨酶(ALT)、谷草转氨酶(AST)、γ-谷氨酰基转肽酶(γ-GT)、总胆固醇(TC)、甘油三酯(TG)、高/低密度脂蛋白胆固醇(H/LDL-C)含量;HE染色观察肝脏结构变化,Western blot检测肝组织PPARα 、FAS、TNF-α蛋白水平,mRNA表达谱测序分析后RT-PCR验证miR-34a、PPARα 、FAS、TNF-α、CPT-1 mRNA表达。结果: 相比K组,AFLD组肝索紊乱,出现灶性脂质真空化,脂滴空泡样变明显,胞核畸形异位;肝功能水平显著降低(P<0.01)。相比M组,ME、HE组肝功能改善显著,血清TG、TC、LDL-C水平下降,HDL-C水平上升(P<0.01或P<0.05),肝脏指数、内脏脂肪比降低(P<0.01),肝细胞灶性脂滴样变下降,肝索结构较清晰;且ME组干预效果更为显著,肝组织PPARα蛋白表达水平上升 、FAS、TNF-α蛋白表达水平下降(P<0.01或P<0.05);基于Illumina高通量测序及mRNA差异分析,PPARα通路中有38个差异表达基因,含9个上调基因,29个下调基因,涉及肝脏脂肪酸氧化、脂质代谢、凋亡抑制等。相比M组,LE、ME、HE组miR-34a、FAS、TNF-α基因水平降低,PPARα、CPT-1基因水平升高(P<0.01或P<0.05)。结论: 不同负荷游泳运动对AFLD小鼠肝功能具有改善作用,促进脂滴降解,调节肝脏脂质代谢,可能与miR-34a/PPARα的激活有关,且中等负荷游泳运动干预效果更佳。     

CD36基因缺失改善高脂饮食诱导的糖代谢异常并促进肝脏脂质积聚

本研究旨在探讨在高脂饮食状态下CD36基因缺失对小鼠糖脂代谢的影响及作用机制。根据基因型将小鼠分为野生型小鼠(wild type, WT)及CD36基因敲除(CD36~(-/-))小鼠,给予高脂饮食喂养14周。小鼠腹腔注射葡萄糖(1 g/kg)或胰岛素(5units/kg)进行葡萄糖耐量或胰岛素耐量测试。HE染色观察肝脏脂质变性,全自动生化分析仪测定小鼠血清甘油三酯(triglyceride, TG)、血清游离脂肪酸(free fatty acid, FFA)、天门冬氨酸转氨酶(aspartate aminotransferase, AST)和丙氨酸转氨酶(alanine aminotransferase, ALT)浓度。Real-time PCR和Western blot检测小鼠肝脏、肌肉组织胰岛素信号通路。Real-time PCR检测小鼠原代肝细胞中磷酸烯醇式丙酮酸羧激酶(phosphoenolpyruvate carboxykinase, PEPCK)的mRNA水平,葡萄糖检测试剂盒检测糖异生能力。免疫共沉淀(co-immunoprecipitation, Co-IP)及ELISA检测肌肉胰岛素受体β(insulin receptorβ, IRβ)酪氨酸磷酸化水平。Real-time PCR和免疫荧光染色检测小鼠肌肉葡萄糖转运蛋白4 (glucose transporter 4, GLUT4)的表达和定位。结果显示,在高脂喂养后,CD36~(-/-)小鼠血清FFA、TG、AST及ALT水平较WT小鼠明显升高(P 0.05),CD36~(-/-)小鼠肝脏外观呈脂肪样变性,HE染色结果显示肝脏脂质积聚加重,提示CD36缺失促进脂肪肝的发生。然而,相对于WT小鼠,CD36~(-/-)小鼠的空腹血糖水平降低、糖耐量升高,胰岛素耐量降低(P 0.05),提示在高脂饮食喂养条件下,CD36缺失并不会损害小鼠的糖耐量和胰岛素耐量。与WT小鼠相比,CD36~(-/-)小鼠肝脏IR/IRS/AKT胰岛素信号通路无显著差异,两组小鼠原代肝细胞PEPCK表达水平及糖异生能力均无显著差异。而在CD36~(-/-)小鼠肌肉组织中,Co-IP及ELISA实验显示IRβ酪氨酸磷酸化水平显著升高,p-AKT水平显著升高(P 0.05)。免疫荧光染色实验提示肌肉GLUT4在细胞膜的定位增强,表明CD36~(-/-)小鼠肌肉胰岛素敏感性及葡萄糖利用能力增强。以上结果提示,CD36基因缺失加重高脂饮食诱导的肝脏脂质积聚,对高脂饮食诱导的肝脏糖代谢无显著影响;CD36缺失主要通过提高肌肉组织胰岛素敏感性,促进GLUT4介导的葡萄糖利用以改善高脂饮食诱导的小鼠糖代谢异常。     

Leptin介导的JAK/STAT信号通路对脂类代谢调节的研究进展

Leptin介导的JAK/STAT信号通路主要参与脂类代谢的调节。JAK/STAT信号通路激活后,CPT-1的表达水平升高,通过促进脂肪酸分解而参与脂类代谢的调节。本文主要介绍了近年来关于leptin介导的JAK/STAT信号通路的组成、作用机制、活性调节和leptin与受体结合激活细胞内多个信号通路如JAK/STAT、PI3K/Akt、MAPK等,以及这些信号通路对脂类代谢调节的最新研究进展。     

Increased Adiposity in Annexin A1-Deficient Mice

Production of Annexin A1 (ANXA1), a protein that mediates the anti-inflammatory action of glucocorticoids, is altered in obesity, but its role in modulation of adiposity has not yet been investigated. The objective of this study was to investigate modulation of ANXA1 in adipose tissue in murine models of obesity and to study the involvement of ANXA1 in diet-induced obesity in mice. Significant induction of ANXA1 mRNA was observed in adipose tissue of both C57BL6 and Balb/c mice with high fat diet (HFD)-induced obesity versus mice on chow diet. Upregulation of ANXA1 mRNA was independent of leptin or IL-6, as demonstrated by use of leptin-deficient ob/ob mice and IL-6 KO mice. Compared to WT mice, female Balb/c ANXA1 KO mice on HFD had increased adiposity, as indicated by significantly elevated body weight, fat mass, leptin levels, and adipocyte size. Whereas Balb/c WT mice upregulated expression of enzymes involved in the lipolytic pathway in response to HFD, this response was absent in ANXA1 KO mice. A significant increase in fasting glucose and insulin levels as well as development of insulin resistance was observed in ANXA1 KO mice on HFD compared to WT mice. Elevated plasma corticosterone levels and blunted downregulation of 11-beta hydroxysteroid dehydrogenase type 1 in adipose tissue was observed in ANXA1 KO mice compared to diet-matched WT mice. However, no differences between WT and KO mice on either chow or HFD were observed in expression of markers of adipose tissue inflammation.These data indicate that ANXA1 is an important modulator of adiposity in mice, with female ANXA1 KO mice on Balb/c background being more susceptible to weight gain and diet-induced insulin resistance compared to WT mice, without significant changes in inflammation.     

Sustained activation of PPARα by endogenous ligands increases hepatic fatty acid oxidation and prevents obesity in ob/ob mice

Obesity, a major health concern, results from an imbalance between energy intake and expenditure. Leptin-deficient ob/ob mice are paradigmatic of obesity, resulting from excess energy intake and storage. Mice lacking acyl-CoA oxidase 1 (Acox1), the first enzyme of the peroxisomal fatty acid β-oxidation system, are characterized by increased energy expenditure and a lean body phenotype caused by sustained activation of peroxisome proliferator-activated receptor α (PPARα) by endogenous ligands in liver that remain unmetabolized in the absence of Acox1. We generated ob/ob mice deficient in Acox1 (Acox1(-/-)) to determine how the activation of PPARα by endogenous ligands might affect the obesity of ob/ob mice. In contrast to Acox1(-/-) (14.3±1.2 g at 6 mo) and the Acox1-deficient (ob/ob) double-mutant mice (23.8±4.6 g at 6 mo), the ob/ob mice are severely obese (54.3±3.2 g at 6 mo) and had significantly more (P<0.01) epididymal fat content. The resistance of Acox1(-/-)/ob/ob mice to obesity is due to increased PPARα-mediated up-regulation of genes involved in fatty acid oxidation in liver. Activation of PPARα in Acox1-deficient ob/ob mice also reduces serum glucose and insulin (P<0.05) and improves glucose tolerance and insulin sensitivity. Further, PPARα activation reduces hepatic steatosis and increases hepatocellular regenerative response in Acox1(-/-)/ob/ob mice at a more accelerated pace than in mice lacking only Acox1. However, Acox1(-/-)/ob/ob mice manifest hepatic endoplasmic reticulum (ER) stress and also develop hepatocellular carcinomas (8 of 8 mice) similar to those observed in Acox1(-/-) mice (10 of 10 mice), but unlike in ob/ob (0 of 14 mice) and OB/OB (0 of 6 mice) mice, suggesting that superimposed ER stress and PPARα activation contribute to carcinogenesis in a fatty liver. Finally, absence of Acox1 in ob/ob mice can impart resistance to high-fat diet (60% fat)-induced obesity, and their liver had significantly (P<0.01) more cell proliferation. These studies with Acox1(-/-)/ob/ob mice indicate that sustained activation of lipid-sensing nuclear receptor PPARα attenuates obesity and restores glucose homeostasis by ameliorating insulin resistance but increases the risk for liver cancer development, in part related to excess energy combustion.     

Voglibose administration regulates body weight and energy intake in high fat-induced obese mice

We tested whether long-term administration of voglibose (VO) prevents diet induced obesity in addition to hypoglycemic effects in high fat fed mice and further investigated the underlying mechanisms by which voglibose exerts its weight lowering effect. Male C57BL/6 mice were fed ad libitum for 12 weeks with the control diet (CTL), high-fat diet (HFD) or the HFD with VO supplementations. Blood lipid profile, plasma leptin levels and hepatic triglyceride content, as well as expressions of genes involved in appetite and mitochondrial function were examined. The results showed that VO significantly reduced body weight, fat mass and energy intakes in high fat fed mice. VO showed improved metabolic profiles including blood glucose, triglyceride and free fatty acid. Elevated levels of plasma leptin in HFD were significantly reduced with the VO, furthermore, VO modulated the hypothalamic expressions of leptin receptors and appetite related genes. VO showed the upregulated expressions of PGC-1 in the liver and epididymal adipose tissue. In conclusion, VO may exert antiobesity properties through reductions in energy intake and improvement in mitochondrial function, indicating that VO has potential therapeutic use in patients with obesity, type 2 diabetes, and related complications.     

β‐Aminoisobutyric Acid Prevents Diet‐induced Obesity in Mice With Partial Leptin Deficiency

β‐Aminoisobutyric acid (BAIBA), a thymine catabolite, increases fatty acid oxidation (FAO) in liver and reduces the gain of body fat mass in Swiss (lean) mice fed a standard chow. We determined whether BAIBA could prevent obesity and related metabolic disorders in different murine models. To this end, BAIBA (100 or 500 mg/kg/day) was administered for 4 months in mice totally deficient in leptin (ob/ob). BAIBA (100 mg/kg/day) was also given for 4 months in wild‐type (+/+) mice and mice partially deficient in leptin (ob/+) fed a high‐calorie (HC) diet. BAIBA did not limit obesity and hepatic steatosis in ob/ob mice, but reduced liver cytolysis and inflammation. In ob/+ mice fed the HC diet, BAIBA fully prevented, or limited, the gain of body fat, steatosis and necroinflammation, glucose intolerance, and hypertriglyceridemia. Plasma β‐hydroxybutyrate was increased, whereas expression of carnitine palmitoyltransferase‐1 was augmented in liver and white adipose tissue. Acetyl‐CoA carboxylase was more phosphorylated, and de novo lipogenesis was less induced in liver. These favorable effects of BAIBA in ob/+ mice were associated with a restoration of plasma leptin levels. The reduction of body adiposity afforded by BAIBA was less marked in +/+ mice. Finally, BAIBA significantly stimulated the secretion of leptin in isolated ob/+ adipose cells, but not in +/+ cells. Thus, BAIBA could limit triglyceride accretion in tissues through a leptin‐dependent stimulation of FAO. As partial leptin deficiency is not uncommon in the general population, supplementation with BAIBA may help to prevent diet‐induced obesity and related metabolic disorders in low leptin secretors.     

Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores

Growing evidences indicate that proteases are implicated in adipogenesis and in the onset of obesity. We previously reported that the cysteine protease cathepsin K (ctsk) is overexpressed in the white adipose tissue (WAT) of obese individuals. We herein characterized the WAT and the metabolic phenotype of ctsk deficient animals (ctsk-/-). When the growth rate of ctsk-/- was compared to that of the wild type animals (WT), we could establish a time window (5-8 weeks of age) within which ctsk-/-display significantly lower body weight and WAT size as compared to WT. Such a difference was not observable in older mice. Upon treatment with high fat diet (HFD) for 12 weeks ctsk-/- gained significantly less weight than WT and showed reduced brown adipose tissue, liver mass and a lower percentage of body fat. Plasma triglycerides, cholesterol and leptin were significantly lower in HFD-fed-ctsk-/- as compared to HFD-fed WT animals. Adipocyte lipolysis rates were increased in both young and HFD-fed-ctsk-/-, as compared to WT. Carnitine palmitoyl transferase-1 activity, was higher in mitochondria isolated from the WAT of HFD treated ctsk-/- as compared to WT. Together, these data indicate that ctsk ablation in mice results in reduced body fat content under conditions requiring a rapid accumulation of fat stores. This observation could be partly explained by an increased release and/or utilization of FFA and by an augmented ratio of lipolysis/lipogenesis. These results also demonstrate that under a HFD, ctsk deficiency confers a partial resistance to the development of dyslipidemia.     

Altered food consumption in mice lacking lysophosphatidic acid receptor-1

The release of lysophosphatidic acid (LPA) by adipocytes has previously been proposed to play a role in obesity and associated pathologies such as insulin resistance and diabetes. In the present work, the sensitivity to diet-induced obesity was studied in mice lacking one of the LPA receptor subtype (LPA1R). Conversely to what was observed in wild type (WT) mice, LPA1R-KO-mice fed a high fat diet (HFD) showed no significant increase in body weight or fat mass when compared to low fat diet (LFD). In addition, in contrast to what was observed in WT mice, LPA1R-KO mice did not exhibit over-consumption of food associated with HFD. Surprisingly, when fed a LFD, LPA1R-KO mice exhibited significant higher plasma leptin concentration and higher level of adipocyte leptin mRNA than WT mice. In conclusion, LPA1R-KO mice were found to be resistant to diet-induced obesity consecutive to a resistance to fat-induced over-consumption of food that may result at least in part from alterations in leptin expression and production.     

Neonatal exposure to leptin augments diet-induced obesity in leptin-deficient Ob/Ob mice

Objective: Epidemiological evidence has revealed that undernutrition in utero is closely associated with obesity and related detrimental metabolic sequelae in adulthood. Recently, using a wild‐type (wt) mouse model in which offspring were exposed to intrauterine undernutrition (UN offspring), we reported that the premature leptin surge during neonatal growth promotes lifelong changes in energy regulating circuitry in the hypothalamus, thus playing an important role in the development of pronounced obesity on a high‐fat diet (HFD) in adulthood. Here, we further evaluate the essential involvement of leptin in the developmental origins of obesity using leptin‐deficient ob/ob mice. Methods and Procedures: We assessed the progression of obesity on an HFD in adult leptin‐deficient ob/ob male mice that were exposed to intrauterine undernutrition by maternal food restriction (ob/ob UN offspring) or to leptin treatment during the neonatal period; this treatment is comparable to the premature leptin surge observed in the wt‐UN offspring. Results: On an HFD, the body weight of the male ob/ob UN offspring paralleled that of the ob/ob offspring exposed to normal intrauterine nutrition (ob/ob NN offspring). In contrast, early exposure to leptin in the ob/ob NN offspring during early neonatal growth reproduced the development of pronounced obesity on an HFD in adulthood. Discussion: The presence of leptin and associated energy regulation are indispensable in the acceleration of obesity on an HFD caused by undernutrition in utero. The premature leptin surge plays an essential role in the developmental origins of obesity as a programming signal during the early neonatal period.     

Catestatin (chromogranin A(352-372)) and novel effects on mobilization of fat from adipose tissue through regulation of adrenergic and leptin signaling

Chromogranin A knock-out (Chga-KO) mice display increased adiposity despite high levels of circulating catecholamines and leptin. Consistent with diet-induced obese mice, desensitization of leptin receptors caused by hyperleptinemia is believed to contribute to the obese phenotype of these KO mice. In contrast, obesity in ob/ob mice is caused by leptin deficiency. To characterize the metabolic phenotype, Chga-KO mice were treated with the CHGA-derived peptide catestatin (CST) that is deficient in these mice. CST treatment reduced fat depot size and increased lipolysis and fatty acid oxidation. In liver, CST enhanced oxidation of fatty acids as well as their assimilation into lipids, effects that are attributable to the up-regulation of genes promoting fatty acid oxidation (Cpt1α, Pparα, Acox, and Ucp2) and incorporation into lipids (Gpat and CD36). CST did not affect basal or isoproterenol-stimulated cAMP production in adipocytes but inhibited phospholipase C activation by the α-adrenergic receptor (AR) agonist phenylephrine, suggesting inhibition of α-AR signaling by CST. Indeed, CST mimicked the lipolytic effect of the α-AR blocker phentolamine on adipocytes. Moreover, CST reversed the hyperleptinemia of Chga-KO mice and improved leptin signaling as determined by phosphorylation of AMPK and Stat3. CST also improved peripheral leptin sensitivity in diet-induced obese mice. In ob/ob mice, CST enhanced leptin-induced signaling in adipose tissue. In conclusion, our results implicate CST in a novel pathway that promotes lipolysis and fatty acid oxidation by blocking α-AR signaling as well as by enhancing leptin receptor signaling.     

The essential function of CARD9 in diet‐induced inflammation and metabolic disorders in mice

Inflammation and metabolic disorder are common pathophysiological conditions, which play a vital role in the development of obesity and type 2 diabetes. The purpose of this study was to explore the effects of caspase recruitment domain (CARD) 9 in the high fat diet (HFD)‐treated mice and attempt to find a molecular therapeutic target for obesity development and treatment. Sixteen male CARD9^?/? and corresponding male WT mice were fed with normal diet or high fat diet, respectively, for 12 weeks. Glucose tolerance, insulin resistance, oxygen consumption and heat production of the mice were detected. The CARD9/MAPK pathway‐related gene and protein were determined in insulin‐responsive organs using Western blotting and quantitative PCR. The results showed that HFD‐induced insulin resistance and impairment of glucose tolerance were more severe in WT mice than that in the CARD9^?/? mice. CARD9 absence significantly modified O₂ consumption, CO₂ production and heat production. CARD9^?/? mice displayed the lower expression of p38 MAPK, JNK and ERK when compared to the WT mice in both HFD‐ and ND‐treated groups. HFD induced the increase of p38 MAPK, JNK and ERK in WT mice but not in the CARD9^?/? mice. The results indicated that CARD9 absence could be a vital protective factor in diet‐induced obesity via the CARD9/MAPK pathway, which may provide new insights into the development of gene knockout to improving diet‐induced obesity and metabolism disorder.     

Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice

Obesity is associated with metabolic disorders. Sulforaphane, an isothiocyanate, inhibits adipogenesis and the occurrence of cardiovascular disease. In this study, we investigated whether sulforaphane could prevent high-fat diet (HFD)-induced obesity in C57BL/6N mice. Mice were fed a normal diet (ND), HFD or HFD plus 0.1% sulforaphane (SFN) for 6 weeks. Food efficiency ratios and body weight were lower in HFD-SFN-fed mice than in HFD-fed mice. SFN attenuated HFD-induced visceral adiposity, adipocyte hypertrophy and fat accumulation in the liver. Serum total cholesterol and leptin, and liver triglyceride levels were lower in HFD-SFN-fed mice than in HFD-fed mice. SFN decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and leptin in the adipose tissue of HFD-SFN mice and increased adiponectin expression. Phosphorylation of AMP-activated protein kinase α (AMPKα) and acetyl-CoA carboxylase in the adipose tissue of HFD-SFN-fed mice was elevated, and HMG-CoA reductase expression was decreased compared with HFD-fed mice. Thus, these results suggest that SFN may induce antiobesity activity by inhibiting adipogenesis through down-regulation of PPARγ and C/EBPα and by suppressing lipogenesis through activation of the AMPK pathway.