二氢杨梅素对高脂饮食诱导的小鼠肥胖的影响及其机制

目的:观察二氢杨梅素(DHM)对高脂饮食诱导小鼠肥胖的影响,并探讨其作用机制是否与促进WAT棕色化有关。方法:60只c57bl/6j小鼠随机分为6组(n=10):①正常对照组(ND组):普通饲料喂养、②正常对照+低剂量DHM组(ND+L-DHM组):普通饲料喂养同时用低剂量DHM(125 mg/(kg·d))处理、③正常对照+高剂量DHM组(ND+H-DHM组):普通饲料喂养同时用高剂量DHM(250 mg/(kg·d))处理、④高脂饮食组(HFD):高脂饲料喂养、⑤高脂饮食+低剂量DHM组(HFD+L-DHM组):高脂饲料喂养同时用低剂量DHM处理、⑥高脂饮食+高剂量DHM组(HFD+H-DHM组):高脂饲料喂养同时用高剂量DHM处理。16周后小鼠空腹过夜,取血测空腹血糖和血脂,随后处死动物,测体长,算出Lee's指数;取肩胛下、腹股沟和附睾处脂肪组织称重后,甲醛固定、HE染色观察脂肪细胞大小,免疫组化检测解偶联蛋白1(UCP1)的表达;实验期间每4周测一次小鼠体重。结果:与ND组相比较,HFD组小鼠体重显著升高,提示肥胖小鼠模型复制成功。此外,HFD组小鼠体脂重量、脂肪细胞直径、Lee's指数和血糖显著增加、脂肪细胞UCP1的表达升高;使用L-DHM和H-DHM处理HFD小鼠后,体脂重量、脂肪细胞直径、Lee's指数和血糖等指标显著逆转,而脂肪细胞UCP1的表达升高更为显著;但L-DHM和H-DHM对正常小鼠上述指标无显著影响。结论:二氢杨梅素抑制高脂饮食诱导的小鼠肥胖,其机制可能与促进WAT棕色化有关。     

肥胖及2型糖尿病患者内脏脂肪基因差异表达研究

目的：筛查在正常人、单纯性肥胖患者及肥胖伴2型糖尿病患者内脏脂肪组织中差异表达的基因。方法：利用自制的高密度cDNA芯片,比较正常人、单纯性肥胖患者及肥胖伴2型糖尿病患者内脏脂肪组织中差异表达的基因,以寻找脂肪组织特异的与肥胖及糖尿病发生有关的基因。结果：和正常人相比,在肥胖患者及肥胖伴2型糖尿病患者中上调的基因分别有119个和257个,下调的基因分别有46和58个。这些基因中有77个在两组中均上调,其中包括与代谢有关的基因,如丙酮酸脱氢酶激酶4（PDK4）以及窖蛋白、金属硫因蛋白等;8个基因在两组中均下调,其中包括脂肪合成途径中的关键酶,如3-羟基-3-甲基戊二酸单酰辅酶A（MGA）合成酶、脂肪酸合成酶及硬脂酰辅酶A脱氢酶。另外,酪氨酸-3单加氧酶-色氨酸-5单加氧酶活化蛋白θ（YWHAZ）仅在肥胖伴2型糖尿病患者中上调,而在单纯性肥胖患者中不变,该基因所编码的蛋白在胰岛素信号转导途径中起着负调控的作用。结论：脂肪组织中脂肪生成下降、脂肪酸氧化增加可能是肥胖及2型糖尿病中胰岛素抵抗发生的共同原因,其它基因功能的改变也可能参与了肥胖及2型糖尿病的发生,而胰岛素信号转导受阻可能是肥胖向糖尿病转化的促进因素。对这些基因的进一步研究将有助于更好地了解肥胖及糖尿病的发生机制。     

Peripherally administered baclofen reduced food intake and body weight in db/db as well as diet-induced obese mice

Peripheral administration of baclofen significantly reduced food intake and body weight increase in both diabetic (db/db) and diet-induced obese mice for 5 weeks, whereas it had no significant effects on energy balance in their lean control mice. Despite the decreased body weight, neuropeptide Y expression in the arcuate nucleus was significantly decreased, whereas pro-opiomelanocortin expression was significantly increased by baclofen treatment. These data demonstrate that the inhibitory effects of baclofen on body weight in the obese mice were mediated via the arcuate nucleus at least partially, and suggest that GABA(B) agonists could be a new therapeutic reagent for obesity.     

低氧对肥胖小鼠棕色脂肪组织相关基因表达的影响及其机制

目的：分析肥胖小鼠在低氧暴露后棕色脂肪组织的差异表达基因及通路,以探讨低氧影响棕色脂肪组织活化的机制。方法：30只雄性C57BL/6J小鼠,其中8只为普通对照组（N,n=8）;其余饲喂高脂饲料8周后,肥胖建模成功小鼠随机分为两组：肥胖对照组（OB,n=8）和肥胖低氧组（H,n=8）。H组进行11.2%氧浓度8 h/d,6天/周共4周的低氧暴露。4周后,测试血糖、血脂,取肩胛处棕色脂肪组织进行mRNA表达谱芯片扫描和生物信息学分析。利用KOBAS2.0软件对所筛选差异表达基因,并对参与关键生物过程和信号通路的差异基因进行实时荧光qPCR验证。结果：干预结束后,H组较OB组体重和血脂血糖水平显著降低;OB组较N组的上调差异基因802个,下调1 175个,差异基因的功能主要集中在糖脂合成代谢及免疫炎症反应过程;H组较OB组上调基因297个,下调228个,主要参与的生物过程有糖脂代谢、脂质转运过程、肌肉组织发育过程及脉管系统发育过程;低氧暴露调节肥胖机体棕色脂肪的通路主要集中在HIF-1、PI3K-Akt、FoxO和ErbB信号通路等过程。结论：11.2%氧气暴露可通过调节一系列棕色脂肪相关基因表达而提高棕色脂肪活性,从而下调肥胖机体体重。     

The contribution of visceral fat to improved insulin signaling in Ames dwarf mice

Ames dwarf (Prop1^df, df/df) mice are characterized by growth hormone (GH), prolactin, and thyrotropin deficiency, remarkable extension of longevity and increased insulin sensitivity with low levels of fasting insulin and glucose. Plasma levels of anti‐inflammatory adiponectin are increased in df/df mice, while pro‐inflammatory IL‐6 is decreased in plasma and epididymal fat. This represents an important shift in the balance between pro‐ and anti‐inflammatory adipokines in adipose tissue, which was not exposed to GH signals during development or adult life. To determine the role of adipose tissue in the control of insulin signaling in these long‐living mutants, we examined the effects of surgical removal of visceral (epididymal and perinephric) adipose tissue. Comparison of the results obtained in df/df mice and their normal (N) siblings indicated different effects of visceral fat removal (VFR) on insulin sensitivity and glucose tolerance. The analysis of the expression of genes related to insulin signaling indicated that VFR improved insulin action in skeletal muscle in N mice. Interestingly, this surgical intervention did not improve insulin signaling in df/df mice skeletal muscle but caused suppression of the signal in subcutaneous fat. We conclude that altered profile of adipokines secreted by visceral fat of Ames dwarf mice may act as a key contributor to increased insulin sensitivity and extended longevity of these animals.     

Metabolic effects of intra-abdominal fat in GHRKO mice

Mice with targeted deletion of the growth hormone receptor (GHRKO mice) are growth hormone (GH) resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long-lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity. Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature, and respiratory quotient (RQ). Overall, VFR produced the expected improvements in insulin sensitivity and reduced body temperature and RQ in normal mice and had opposite effects in GHRKO mice. Some of the examined parameters were altered by VFR in opposite directions in GHRKO and normal mice, and others were affected in only one genotype or exhibited significant genotype × treatment interactions. Functional differences between visceral fat of GHRKO and normal mice were confirmed by measurements of adipokine secretion, lipolysis, and expression of genes related to fat metabolism. We conclude that in the absence of GH signaling, the secretory activity of visceral fat is profoundly altered and unexpectedly promotes enhanced insulin sensitivity. The apparent beneficial effects of visceral fat in GHRKO mice may also explain why reducing adiposity by calorie restriction fails to improve insulin signaling or further extend longevity in these animals.     

Capsaicin suppresses liver fat accumulation in high-fat diet-induced NAFLD mice

ABSTRACT

Dietary capsaicin exhibits anti-steatosis activity in obese mice. High-fat diet (HFD)-induced mice is a highly studied approach to develop non-alcoholic fatty liver disease (NAFLD). In this study, we determined whether the topical application of capsaicin can improve lesions of NAFLD. The HFD-induced mice were treated with daily topical application of capsaicin for 8 weeks. Topical application of capsaicin reduced liver fat in HFD-fed mice. Capsaicin stimulated carnitine palmitoyl transferase (CPT)-1 and CD36 expression, which are associated with β-oxidation and fatty acids influx of liver while it decreased the expression of key enzymes involved in the synthesis of fatty acids, such as acetyl Co-A carboxylase (ACC) and fatty acid synthase (FAS). Immunohistochemical analysis revealed the elevated level of adiponectin in liver tissue of the capsaicin-treated mice. These results suggest that the topical application of capsaicin suppresses liver fat accumulation through the upregulation of β-oxidation and de novo lipogenesis in HFD-induced NAFLD mice.     

Central administration of melanocortin agonist increased insulin sensitivity in diet-induced obese rats

In this study, we examined the effects of intracerebroventricular administration of melanotan II (MTII), a melanocortin agonist, on insulin sensitivity in diet-induced obese (DIO) rats. Although MTII treatment significantly decreased food intake and body weight for 10 days, there was no significant difference in body weight between MTII and pair-fed groups. The insulin tolerance test showed that insulin sensitivity was significantly improved in the MTII group compared to the pair-fed group. Furthermore, MTII treatment increased the number of small-sized adipocytes in epididymal white adipose tissues, suggesting that MTII increased insulin sensitivity through action on the white adipose tissues in DIO rats.     

Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice

Obesity is accompanied by adipocyte death and accumulation of macrophages and mast cells in expanding adipose tissues. Considering the differences in biological behavior of fat found in different anatomical locations, we explored the distribution of mast cells, solitary macrophages, and crown-like structures (CLS), the surrogates for dead adipocytes, in subcutaneous and abdominal visceral fat of lean and diet-induced obese C57BL/6 mice. In fat depots of lean mice, mast cells were far less prevalent than solitary macrophages. Subcutaneous fat contained more mast cells, but fewer solitary macrophages and CLS, than visceral fat. Whereas no significant change in mast cell density of subcutaneous fat was observed, obesity was accompanied by a substantial increase in mast cells in visceral fat. CLS became prevalent in visceral fat of obese mice, and the distribution paralleled mast cells. Adipose tissue mast cells contained and released preformed TNF-α, the cytokine implicated in the pathogenesis of obesity-linked insulin resistance. In summary, subcutaneous fat differed from visceral fat by immune cell composition and a lower prevalence of CLS both in lean and obese mice. The increase in mast cells in visceral fat of obese mice suggests their role in the pathogenesis of obesity and insulin resistance.     

Ultrasonographic measurements of localized fat accumulation in Shetland pony mares fed a normal v. a high energy diet for 2 years

Health risks associated with obesity are more likely a factor of the localization of fat excess, rather than of elevated BW per se. The aim of this randomized controlled clinical trial was to determine the effect of a long-term high energy diet on BW, fat accumulation and localization. Eight Shetland pony mares, 3 to 7 years old, were randomly divided into a control and a high energy (HE) diet group fed either maintenance or double maintenance energy requirements (200% net energy (NE)) for two consecutive summers, with a low energy diet in the winter in between. Body condition score (BCS) did not differ between the groups at the onset of the study (control 5.6±0.75 v. HE 6.3±0.5). From 12 weeks after starting the diet, ultrasonography of five different locations (retroperitoneal, axillary, withers, intercostal and rump) for adipose deposition, BCS and BW were measured monthly during the period that ponies received different diets. Statistical analysis was performed using a linear mixed-effects model with post hoc Bonferroni testing. P values <0.05 were considered significant. At week 12 after the onset of the diet, fat thickness in the HE group was significantly greater than in the control group. During the monitoring period, the HE group showed a significant increase in mean (±SE) BW (+52%, 265±13.94kg) and BCS (+70%; to 9.0±0.4), while the control group was unchanged (BW 160±13.98 kg; BCS 3.8±0.4). At all locations, the fat depth in the HE group increased significantly, with the highest increase noted for retroperitoneal deposits. The conclusions were that a 200% NE diet induced subcutaneous and retroperitoneal fat accumulation, with the greatest increase in intra-abdominal deposits. The moderate increase of the subcutaneous fat depth followed by a plateau phase suggests the existence of a limit of adipose tissue expandability, as in man.     

Lipolysis-derived linoleic acid drives beige fat progenitor cell proliferation

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