Corn gluten hydrolysate and capsaicin have complimentary actions on body weight reduction and lipid-related genes in diet-induced obese rats

The aim of this study was to test the hypothesis that a combination of corn gluten hydrolysate (CGH) and capsaicin may have an additive or synergistic effect on body weight reduction. For 13 weeks, male Sprague-Dawley rats were provided a diet to induce obesity. Afterward, the rats were randomly divided into 5 dietary groups: the normal control (n = 5), the high-fat control (n = 8), the high-fat diet (HFD) containing 35% CGH (n = 7), the HFD containing 0.02% capsaicin (HF-P) (n = 8), and the HFD containing both CGH and capsaicin (HF-CP) (n = 7) for an additional 4 weeks. Administration of CGH plus capsaicin, along with a HFD, led to significant decreases in body weight, fat mass, lipids in the liver, and plasma leptin as well as increases in plasma adiponectin. The pattern of gene expression was different in each target organ. In the liver, up-regulation of peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1α, and acyl-coenzyme A oxidase was found in the HF-CP group. In contrast, down-regulation of peroxisome proliferator-activated receptor γ was found in both the HFD containing 35% CGH and HF-CP groups. In skeletal muscle, up-regulation of insulin receptor and uncoupling protein 3 was found in the HF-P group only, whereas up-regulation of the glucose transporter 4 gene was observed in both the HF-CP and HF-P groups. In adipose tissue, up-regulation of peroxisome proliferator-activated receptor γ and hormone-sensitive lipase was only found in the HF-CP group. In summary, this study suggests that CGH and capsaicin perform complementary actions on food intake, lipid metabolism, and insulin sensitivity by a coordinated control of energy metabolism in the liver, adipose tissue, and skeletal muscle, thus exerting an additive effect on body weight reduction.     

有氧运动与平肥方对DIO大鼠脂代谢和胰岛素抵抗的影响

目的评价有氧运动与平肥方对高脂饮食所致肥胖大鼠(DIO)脂肪代谢和胰岛素抵抗的影响。方法 SD雄鼠10只予普饲喂养作为空白对照组,30只经高脂饮食诱导成功的DIO雄鼠随机分为肥胖对照组、二甲双胍组、有氧运动+平肥方干预组,每组10只。实验干预6周后,检测各组大鼠体质量(BW)、空腹血糖(FPG)、总胆固醇(TCH)、甘油三酯(TG)、极低密度脂蛋白(VLDL)、空腹胰岛素(FINS)、HOMA-指数(HOMA-index)等。结果与对照组比较,DIO大鼠体质量、脂代谢各指标、血糖、胰岛素等差异具有统计学意义(P<0.01);干预数周后,与肥胖对照组比较,二甲双胍组和综合组均可显著降低DIO大鼠体质量,并可显著改善脂代谢诸指标及血糖、胰岛素及HOMA-指数(P<0.05或P<0.01)。其中,综合组在改善DIO大鼠体质量、VLDL两指标更优于二甲双胍治疗组(P<0.05)。结论 DIO大鼠普遍存在体质量、脂代谢异常及胰岛素抵抗;有氧运动和中药平肥方结合干预DIO大鼠,相对二甲双胍,在改善胰岛素抵抗的同时,能更好地减轻体质量并改善脂质代谢。     

The role of NPY in hypothalamic mediated food intake

Neuropeptide Y (NPY) is a highly conserved neuropeptide with orexigenic actions in discrete hypothalamic nuclei that plays a role in regulating energy homeostasis. NPY signals via a family of high affinity receptors that mediate the widespread actions of NPY in all hypothalamic nuclei. These actions are also subject to tight, intricate regulation by numerous peripheral and central energy balance signals. The NPY system is embedded within a densely-redundant network designed to ensure stable energy homeostasis. This redundancy may underlie compensation for the loss of NPY or its receptors in germline knockouts, explaining why conventional knockouts of NPY or its receptors rarely yield a marked phenotypic change. We discuss insights into the hypothalamic role of NPY from studies of its physiological actions, responses to genetic manipulations and interactions with other energy balance signals. We conclude that numerous approaches must be employed to effectively study different aspects of NPY action.     

The utility of animal models to evaluate novel anti-obesity agents

The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic.     

The cannabinoid Δ9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity

Background:

Cannabinoid type-1 (CB1) receptor inverse agonists improve type 2 diabetes and dyslipidaemia but were discontinued due to adverse psychiatric effects. Δ⁹-Tetrahydrocannabivarin (THCV) is a neutral CB1 antagonist producing hypophagia and body weight reduction in lean mice. We investigated its effects in dietary-induced (DIO) and genetically (ob/ob) obese mice.

Methods:

We performed two dose-ranging studies in DIO mice; study 1: 0.3, 1, 2.5, 5 and 12.5 mg kg⁻¹, oral twice daily for 30 days and study 2: 0.1, 0.5, 2.5 and 12.5 mg kg⁻¹, oral, once daily for 45 days. One pilot (study 3: 0.3 and 3 mg kg⁻¹, oral, once daily) and one full dose-ranging (study 4: 0.1, 0.5, 2.5 and 12.5 mg kg⁻¹, oral, once daily) studies in ob/ob mice for 30 days. The CB1 inverse agonist, AM251, oral, 10 mg kg⁻¹ once daily or 5 mg kg⁻¹ twice daily was used as the positive control. Cumulative food and water intake, body weight gain, energy expenditure, glucose and insulin levels (fasting or during oral glucose tolerance tests), plasma high-density lipoprotein and total cholesterol, and liver triglycerides were measured. HL-5 hepatocytes or C₂C₁₂ myotubes made insulin-resistant with chronic insulin or palmitic acid were treated with 0, 1, 3 and 10 μℳ THCV or AM251.

Results:

THCV did not significantly affect food intake or body weight gain in any of the studies, but produced an early and transient increase in energy expenditure. It dose-dependently reduced glucose intolerance in ob/ob mice and improved glucose tolerance and increased insulin sensitivity in DIO mice, without consistently affecting plasma lipids. THCV also restored insulin signalling in insulin-resistant hepatocytes and myotubes.

Conclusions:

THCV is a new potential treatment against obesity-associated glucose intolerance with pharmacology different from that of CB1 inverse agonists/antagonists.     

Reduction of hepatosteatosis and lipid levels by an adipose differentiation-related protein antisense oligonucleotide

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive triglyceride accumulation in hepatocytes. Expression of the lipid droplet protein adipose differentiation-related protein (ADRP) is increased in NAFLD, but whether this is causally linked to hepatic lipid metabolism is unclear. We postulated that a reduction in ADRP would ameliorate hepatic steatosis and improve insulin action. METHODS: Leptin deficient Lep(ob/ob) and diet-induced obese (DIO) mice were treated with antisense oligonucleotide (ASO) against ADRP, and effects on hepatic and serum lipids and glucose homeostasis were examined. RESULTS: ADRP ASO specifically decreased ADRP mRNA and protein levels in the livers of Lep(ob/ob) and DIO mice, without altering the levels of other lipid droplet proteins, that is, S3-12 and TIP47. ADRP ASO suppressed expression of lipogenic genes, reduced liver triglyceride content without affecting cholesterol, attenuated triglyceride secretion, and decreased serum triglyceride and alanine aminotransaminase levels. The reduction in hepatic steatosis by ADRP ASO was associated with improvement in glucose homeostasis in both Lep(ob/ob) and DIO mice. CONCLUSIONS: This study demonstrates a crucial role for the lipid droplet protein ADRP in regulation of lipid metabolism. Reduction in hepatic ADRP level using an antisense oligonucleotide reverses hepatic steatosis, hypertriglyceridemia, and insulin resistance in obese mice, suggesting that ADRP may be targeted for the treatment of NAFLD and associated lipid and glucose abnormalities.     

肥胖大鼠模型的建立及其脂代谢相关分子机制研究

目的建立饮食诱导的肥胖(diet-induced obesity, DIO)大鼠模型并初步探讨其发病的分子机制。方法用脂肪含量30%的高脂饲料饲喂雄性SD大鼠25周,观察大鼠体重、Lee''s指数、肝组织病理改变,检测大鼠空腹血糖及空腹血清胰岛素水平,并通过real-time PCR,检测成模大鼠肝脏中乙酰辅酶A羧化酶(ACC)、脂肪酸合酶(FAS)、激素敏感酯酶(HSL)以及固醇调节元件结合蛋白-1c(SREBP-1c)的表达变化。结果高脂饲料饲喂6周后,DIO组大鼠体重、Lee''s指数均显著增加；25周后肝脏脂肪异常蓄积,出现中重度脂肪肝,空腹血糖及胰岛素水平显著升高,出现明显的胰岛素抵抗。肝脏中ACC、FAS和HSL表达显著增加,SREBP-1c表达水平达到正常组的2.56倍,两组间差异极其显著。结论成功建立了DIO大鼠模型,通过检测脂代谢相关基因的表达水平,初步阐释了营养性肥胖的发生与脂代谢变化之间的关系, SREBP-1c, ACC, FAS和HSL参与了DIO的形成,从而初步揭示了脂代谢变化与营养性肥胖的发生的关系。     

Diets containing Sophora japonica L. prevent weight gain in high-fat diet-induced obese mice

Obesity, a worldwide epidemic, is associated with metabolic diseases such as insulin resistance, dyslipidemia, hypertension, and heart disease. Many strategies, including natural alternative antiobesity agents, have been widely used to prevent obesity. Polyphenolic compounds and flavonoids from natural products are shown to inhibit adipogenesis. Because mature fruits of Sophora japonica L. were previously shown to contain antiadipogenic compounds, we hypothesized that diets with mature fruits of S japonica L. would prevent body weight gain in high-fat diet–induced obesity. Four-week-old mice were fed either a control high-fat diet, or high-fat diet containing 1% or 5% of S japonica L. for 4 weeks. The administration of S japonica L. fed in combination with a 30% high-fat diet significantly decreased body weight gain. S japonica L. also reduced serum and hepatic triglyceride, serum total, and high-density lipoprotein cholesterol. Consistent with the effects of lowering glucose level and fat mass, S japonica L. caused a decrease in the number of large adipocytes and a concomitant increase in the number of small adipocytes, which may explain at least in part the antiobesity effects of S japonica L. Together, these data provide evidence for roles of S japonica L. in the control of body weight and obesity-related metabolic diseases.     

Anti-obesity effects of KR-66195, a synthetic DPP-IV inhibitor,in diet-induced obese mice and obese-diabetic ob/ob mice

Objective

We investigated whether KR-66195, a new synthetic dipeptidyl dipeptidase IV inhibitor, could prevent weight gain, as well as improving glycemic control in diet-induced obese (DIO) and ob/ob mice.

Materials/Methods

Male C57BL/6 mice were randomly assigned to the following groups: chow diet, high-fat diet, and high-fat diet with KR-66195. After KR-66195 treatment for eight weeks, intraperitoneal glucose tolerance tests were performed. A pair-feeding study was performed to investigate the mechanisms of the anti-obesity effects of KR-66195 in DIO mice. Female ob/ob mice were treated with KR-66195 for three weeks and compared to the vehicle-treated group.

Results

In DIO mice, KR-66195 treatment increased the plasma glucagon-like peptide (GLP)-1 levels and improved glucose tolerance. This treatment also reduced body weight gain (5.38 ± 0.94 g vs. 12.08 ± 0.55 g, P < 0.01) and food intake (2.41 ± 0.09 g vs. 2.79 ± 0.11 g, P < 0.05). In ob/ob mice, KR-66195 treatment for three weeks resulted in comparable effects in DIO mice. In the pair-feeding study, KR-66195-treated mice exhibited a 16% increase in energy expenditure (kcal/h/kg lean body mass) without significant differences in body weight or activities compared with pair-fed mice. These results suggest that KR-66195 prevented weight gain in DIO mice by decreasing food intake, as well as increasing energy expenditure.

Conclusions

KR-66195 markedly increased plasma levels of GLP-1, resulting in the probable improvement in glucose tolerance and reduced body weight and food intake. Thus, KR-66195 might be further developed as a therapeutic drug to treat obesity, as well as diabetes.     

DIO2基因单核苷酸多态性与精神发育迟滞相关性研究

目的探讨DIO2基因多态性及单倍型与精神发育迟滞的相关关系。方法本研究以344个汉族精神发育迟滞患者及其亲属组成的家系为研究对象．在DIO2上选择了3个合适的SNPs作为标记．利用PCR—SSCP和PCR—RFLP方法完成基因分型。应用FBAT软件对多态位点及可能组成的单倍型与精神发育迟滞的关系进行分析。结果单个位点家系关联性分析结果提示：rs225015、rs225014和rs225012位点各等位基因从亲代传递给患病子代没有观察到显著性（P〉0．05）。多态性位点间的连锁不平衡检验显示：3个位点rs225015、rs225014和rs225012均具有较高的连锁不平衡（D’〉0．8）。单倍型分析结果显示：3个位点构成的单体型GTG在附加遗传模型（Z=2．226,P=0．026019）和隐性遗传模型（Z=2．651,P=0．008023）与MR相关。结论DIO2基因可能与精神发育迟滞的易感性有关。