三七总皂苷对大鼠非酒精性脂肪肝模型胰岛素抵抗及瘦素受体表达的影响

目的 研究三七总皂苷对大鼠脂肪肝模型胰岛素抵抗（IR）及瘦素受体表达的影响，探讨其治疗脂肪肝的作用机制。方法 利用高脂饮食诱发大鼠非酒精性脂肪肝（NAFLD）模型；称各组大鼠体重、肝湿重，计算肝指数；放射免疫法测定血清瘦素（LP）和胰岛素（FINS）浓度，全自动生化分析仪测空腹血糖，计算空腹下胰岛素抵抗指数；免疫组化法检测瘦素受体（OB—R）在肝组织中的表达，图像分析，计算平均光密度值。结果 三七总皂苷高、低剂量组体重及肝指数与模型组比较明显下降（P〈0.05），瘦素水平和胰岛素抵抗指数与模型组比较均有明显降低（P〈0.05），模型组肝组织OB—R表达比正常组明显增强（P〈0.05），三七总皂苷高、低剂量均可下调模型组大鼠OB—R的表达，且高剂量组最为明显（P〈0．05）。结论 三七总皂苷治疗NAFLD有效，并通过降低肝指数、血清瘦素水平，改善胰岛素抵抗和下调瘦素受体表达而起到治疗NAFLD的作用。     

神经肽Y Y5受体基因反义寡核苷酸脑室给药对糖尿病伴缺血再灌注大鼠血清瘦素与胰岛素的影响

目的观察神经肽Y Y5(NPY Y5)受体基因反义寡核苷酸脑室给药对伴糖尿病缺血再灌注大鼠血清瘦素的影响.方法链脲佐菌素空腹腹腔注射制备糖尿病大鼠模型,线栓法闭塞大脑中动脉制作脑缺血再灌注大鼠模型;治疗组经导管向脑室注入50 μg(5 U/μl)NPY Y5受体基因反义寡核苷酸,每天3次给药,连续应用3 d;采用ELISA双抗体夹心法测定血清瘦素含量,放射免疫法测定胰岛素含量.结果缺血再灌注损伤后,大鼠血清瘦素、胰岛素水平较对照组显著升高;NPY Y5受体基因反义脱氧核苷酸侧脑室注射干预后,其血清瘦素、胰岛素水平明显下降.结论神经肽Y Y5受体基因反义寡核苷酸侧脑室给药可降低糖尿病伴缺血再灌注大鼠的血清瘦素、胰岛素水平,改善外周瘦素抵抗与IR,促进脑梗死恢复.     

神经肽Y Y5受体基因反义寡核苷酸脑室给药对肥胖大鼠外周瘦素抵抗的影响

目的 探讨神经肽Y（NPY）Y5受体基因反义寡核苷酸脑室给药对饮食所致肥胖大鼠外周瘦素抵抗的影响。方法 （1）建立高营养饲料诱导的肥胖大鼠模型，侧脑室插管后注射NPY Y5受体基因反义、错义寡核苷酸及生理盐水，观察大鼠腹膜后脂肪湿重的变化；（2）采用ELISA双抗体夹心法测定血清瘦素含量、放免法测定血清胰岛素含量，RT－PCR技术检测脂肪组织中ob基因的表达水平，评价该疗法对肥胖大鼠外周瘦素抵抗的影响。结果 经NPY Y5受体基因反义寡核苷酸干预后，肥胖大鼠腹膜后脂肪湿重、血清胰岛素含量、血清瘦素含量、腹膜后脂肪组织ob基因mRNA表达水平均明显降低，降腹膜后脂肪组织湿重与肥胖错义组差异未达到统计学意义外，其余指标与肥胖盐水组、肥胖错义组相比差异均有显著性，而肥胖错义组与肥胖盐水组之间各观察指标差异均无显著性。结论 侧脑室注射NPY Y5受体基因反义寡核苷酸可显著减少营养性肥胖大鼠的腹膜后脂肪，降低肥胖大鼠脂肪组织ob基因表达及血清瘦素、胰岛素含量，改善外周瘦素抵抗。     

神经肽Y Y5受体基因反义寡核苷酸脑室给药对大鼠血清瘦素、胰岛素及TNF-α水平的影响

目的 观察神经肽Y Y5(NPY Y5)受体基因反义寡核苷酸脑室给药对伴糖尿病缺血再灌注(I/R)大鼠血清瘦素、胰岛素与TNF-α水平的影响.方法 链脲佐菌素空腹腹腔注射制备糖尿病大鼠模型,线栓法闭塞大脑中动脉制作脑I/R大鼠模型;治疗组经导管向脑室注入50 μg(5 μg/μl)NPY Y5受体基因反义寡核苷酸,每天3次给药,连续用药3 d;采用ELISA双抗体夹心法测定血清TNF-α与瘦素含量,放射免疫法测定胰岛素含量. 结果 I/R损伤后,大鼠血清瘦素、胰岛素、TNF-α水平较对照组显著升高(P＜0.05,P＜0.01);NPY Y5受体基因反义脱氧核苷酸侧脑室注射干预后,其血清瘦素、胰岛素水平明显下降(P＜0.05),TNF-α水平显著降低(P＜0.01).结论 神经肽Y Y5受体基因反义寡核苷酸侧脑室给药可降低伴糖尿病I/R大鼠的血清瘦素、TNF-α与胰岛素水平,改善外周瘦素抵抗与胰岛素抵抗(IR),促进脑梗死恢复.     

中医综合减肥法对肥胖症大鼠血浆神经肽Y的影响

目的探讨中医综合疗法对血浆神经肽水平的影响作用。方法将70只SD大鼠随机分成正常对照组、模型对照组、阳性对照组、针灸治疗组、埋线治疗组、中药治疗组、综合治疗组,每组10只。采用营养肥胖造模方法复制肥胖模型大鼠,造模前、后尾静脉取血,放射免疫法检测各组大鼠血浆神经肽含量。结果模型组血浆神经肽水平明显低于正常组（P〈0.05）,综合治疗组体重血浆神经肽水平明显高于模型组（P〈0.01）。结论中医综合疗法的减肥作用机制可能与升高血浆神经肽Y水平有关。     

昆丹颗粒对代谢综合征大鼠模型的影响及机制研究

目的观察昆丹颗粒对代谢综合征大鼠模型的影响及探讨其可能机制。方法 Wistar雄性大鼠随机分组,分为空白对照组和造模组,空白对照组灌胃蒸馏水,造模组灌胃高脂高糖高盐乳剂。造模6周后,将造模成功的大鼠按体重随机分为5组:模型组、昆丹高剂量组、昆丹中剂量组、昆丹低剂量组、罗格列酮组,药物干预6周,在用药期间继续灌胃高脂高糖高盐乳剂。试验结束后,检测体重、空腹血糖、血清胰岛素、计算胰岛素敏感指数(ISI)、血脂、肿瘤坏死因子-α(TNF-α)、游离脂肪酸(FFA)、瘦素(lept)。结果昆丹高剂量组可明显降低代谢综合征大鼠的空腹血糖、血清胰岛素、尾动脉收缩压、TNF-α,升高胰岛素敏感指数;昆丹高、中剂量组可显著降低体重、FFA、瘦素。结论昆丹颗粒具有明显的减重、降糖、调脂、降压作用,其机制可能与降低FFA、TNF-α、Lept的水平,改善胰岛素敏感性有关。     

2型糖尿病患者腹部脂肪分布与胰岛素敏感性及血清瘦素水平的关系

目的 探讨2型糖尿病患者腹部脂肪分布与瘦素和胰岛素抵抗的关系。方法 48例2型糖尿病患者均进行高胰岛素正血糖钳夹试验，根据体重指数(BMI)和葡萄糖利用率(GIR)将患者分为非肥胖型胰岛素敏感组(NIS，16例)，非肥胖型胰岛素抵抗组(NIR，15例)和肥胖型胰岛素抵抗组(OIR，17例)，同时洲定血清瘦素，胰岛素水平和腹部脂肪面积。结果 两非肥胖组(NIS和NIR)之间的BMI相似，但NIR组的GIR要明显低于NIS组，NIR组的内脏脂肪面积比NIS组明显增高，NIR组的瘦素水平在皮下脂肪校正之后与NIS组差异无显著性。OIR组的皮下脂肪，内脏脂肪和瘦素水平比非肥胖组(NIS和NIR)明显增高，OIR的GIR明显低于NIS和NIR组。多元回归分析显示，无论肥胖组还是非肥胖组，内脏脂肪是预测胰岛素抵抗的最重要变量；皮下脂肪是血清瘦素水平的最重要变量。结论 两种代谢不同的脂肪分布是胰岛素抵抗和瘦素水平的决定因素。     

三黄泻心汤对肥胖大鼠血清瘦素及胰岛素水平影响的实验研究

目的通过三黄泻心汤对肥胖大鼠体重、Lee’s指数、腹腔脂肪湿重及血清瘦素、胰岛素水平的影响,探讨清热解毒法对肥胖及瘦素、胰岛素抵抗的调整作用。方法给予高脂饮食建立营养性肥胖大鼠模型,将肥胖大鼠随机分为3组,分别给予三黄泻心汤(A组)、盐酸芬氟拉明(B组)和生理盐水(C组)灌胃,连续12周,每周测体重,试验末取血测血脂、血清瘦素及胰岛素。结果A组和B组大鼠体重分别为(387.8±12.1)g和(378.3±10.7)g较C组的(493.1±8.9)g低(P<0.05);腹腔脂肪湿重A组和B组也较C组低(P<0.01),且随喂养时间的延长体重变化趋势A组下降缓慢,B组亦下降,但试验末略有上升,C组体重继续增长。A组和B组血糖、胆固醇和低密度脂蛋白均较C组低,瘦素和胰岛素的变化A组和B组较C组亦低(P<0.05),且A组与C组血糖和胰岛素差异更大(P<0.01)。结论三黄泻心汤可能通过降低肥胖大鼠体重、血糖及血清瘦素、胰岛素水平而发挥调节血脂、改善瘦素和胰岛素抵抗的作用。     

高果糖膳食对大鼠下丘脑增食欲素系统的影响

增食欲素是涉及摄食及内分泌代谢调控的神经肽。本研究以高果糖饲料诱导胰岛素抵抗(IR)大鼠模型。高胰岛素正葡萄糖钳夹技术证实的胰岛素抵抗 (IR)大鼠模型中增食欲素、瘦素的变化。结果显示 ,高果糖饲料可诱导IR ;破坏增食欲素与瘦素的平衡。血糖、胰岛素、脂代谢及瘦素均可参与增食欲素调控。     

老年人瘦素水平与代谢综合征的关系

目的 研究老年人群血清瘦素水平与肥胖及其它代谢综合征的关系，探讨高瘦素血症是否是代谢综合征的又一重要成分。方法 采用ELISA法测定258例非糖尿病的老年男性的空腹瘦素和真胰岛素水平，分析瘦素水平与血压、血脂、血糖水平以及与定量胰岛素敏感指数(QUICKl)的相关性。结果 肥胖者的瘦素水平是非肥胖者的两倍(7．3ng／m1与3．3ng／m1)；瘦素水平随代谢异常组合个数的增多而依次增加。相关分析显示瘦素与体重指数、腰臀比、真胰岛素、QUICKI、收缩压、甘油三酯和高密度脂蛋白胆固醇(HDL-C)显著相关(|r|＝0．28—0．46，均为P＜0．01)；与血糖的相关性在调整肥胖度后消失，结论 该老年人群的瘦素水平与肥胖、高胰岛素血症／胰岛素抵抗以及代谢综合征的其他成分密切相关，提示高瘦素血症／瘦素抵抗可能是代谢综合征的又一特征，并且可能在代谢综合征的发病中起作用。     

Importance of plasma leptin in predicting future weight gain in obese children: a two-and-a-half-year longitudinal study

OBJECTIVE: To determine whether relatively low leptin levels predict changes in adiposity in prepubertal and pubertal obese children. RESEARCH METHODS AND PROCEDURES: In a biracial cohort of 68 obese children (33 male and 35 female; 46 Caucasians and 22 African-Americans, age range 7-18 y), we measured at baseline fasting insulin and leptin levels, height and weight and calculated body mass index (kg/m(2)) and expressed body mass index as (BMI) Z-score. After a 2.5-y follow-up, anthropometric measurements were repeated and changes in weight gain were calculated as changes in BMI Z-score. RESULTS: At baseline obese preadolescent boys and girls had similar age and BMI Z-score, fasting insulin and leptin levels. After an average follow-up of 2.5 y, mean weight change calculated by changes in BMI Z-score from baseline was similar in both groups. In obese adolescent boys and girls at baseline, no significant gender differences were observed for BMI Z-score and insulin levels. In contrast, plasma leptin levels were significantly higher in obese girls compared with obese adolescent boys. At follow-up, there was no significant difference in change in BMI Z-score between obese boys and girls. Multiple linear regression analysis revealed that high basal leptin levels were positively associated with greater changes in BMI Z-score only in girls (r(2)=0.18, P<0.02), after adjusting for basal BMI Z-score, Tanner stage, years of follow-up and basal insulin. High basal leptin levels in girls explained 18% of the weight gain. CONCLUSION: High leptin levels are associated with excessive future weight gain only in girls.     

Effects of intravenous neuropeptide Y on insulin secretion and insulin sensitivity in skeletal muscle in normal rats

Summary Intracerebroventricular administration of neuropeptide Y to normal rats induces a syndrome characterised by obesity, hyperinsulinaemia, insulin resistance and over expression of the adipose tissue ob gene. Little is known about the effect of circulating neuropeptide Y on glucose metabolism, insulin secretion and leptin. We therefore aimed to evaluate the effect of an intravenous infusion of neuropeptide Y on glucose disposal, endogenous glucose production, whole body glycolytic flux, and glucose storage as assessed during euglycaemic hyperinsulinaemic clamp. In addition, the insulin-stimulated glucose utilisation index in individual tissues was measured by the 2-deoxy-[1-³H]-glucose technique. The effect of neuropeptide Y on insulin secretion was evaluated by hyperglycaemic clamp. Infusion did not induce any change in endogenous glucose production during basal conditions or at the end of the clamp. Glucose disposal was significantly increased in the rats given neuropeptide Y compared with controls (27.8 ± 1.3 vs 24.3 ± 1.6 mg · min^–1· kg^–1; p < 0.05) as was the glycolytic flux (18.9 ± 1.6 vs 14.4 ± 0.8 mg · min^–1· kg^–1; p < 0.05), while glucose storage was comparable in the two groups. In skeletal muscle, the glucose utilisation index was increased significantly in rats given neuropeptide Y. The glucose utilisation index in subcutaneous and epididimal adipose tissue was not significantly different between the two groups. Plasma leptin was significantly increased by hyperinsulinaemia, but was not affected by neuropeptide Y infusion. Both the early and late phase of the insulin response to hyperglycaemia were significantly reduced by neuropeptide Y. In conclusion neuropeptide Y infusion may increase insulin-induced glucose disposal in normal rats, accelerating its utilisation through the glycolytic pathway. Neuropeptide Y reduces both phases of the insulin response to hyperglycaemia. [Diabetologia (1998) 41: 1361–1367] Received: 4 March 1998 and in revised form: 27 May 1998     

Effects of streptozotocin-induced diabetes mellitus and insulin treatment on neuropeptide Y mRNA in the rat hypothalamus

Summary Levels of neuropeptide Y and neuropeptide Y mRNA are increased in the arcuate nucleus of severely diabetic rats which may be the result of the associated marked hypoinsulinaemia. We hypothesised that if neuropeptide Y mRNA is regulated by physiological changes in circulating insulin, then the relatively minor changes in circulating insulin found in mild diabetes would also affect neuropeptide Y expression and its response to changing insulin levels should be rapid. Neuropeptide Y mRNA was quantified by in situ hybridisation through the rostral, mid and caudal levels of the arcuate nucleus of adult female rats. Neuropeptide Y mRNA was significantly increased at all three levels of the arcuate nucleus, 7 days after i.v. administration of 40 mg/kg streptozotocin. Neuropeptide Y mRNA was not further increased in the arcuate nucleus of animals given 50 mg/kg streptozotocin. In the former group, serum glucose was increased but insulin levels and body weights were the same as in control rats. In the 50 mg/kg streptozotocin group, serum glucose was further increased while serum insulin and body weight were reduced. In addition, neuropeptide Y mRNA was not altered in the hypothalamic dorsomedial nucleus or the thalamic reticular nucleus. When diabetic rats were treated for 20h with s.c. insulin, there was decreased neuropeptide Y mRNA in the arcuate nucleus. We conclude that neuropeptide Y mRNA in the arcuate nucleus is responsive to small changes in circulating insulin levels and the response occurs within 20 h. These data support that circulating insulin may contribute to control of neuropeptide Y expression under physiological conditions. Presented in part at the Ninth International Congress of Endocrinology, 1992 Nice, France     

Administration of physiologic levels of triiodothyronine increases leptin expression in calorie-restricted obese rats, but does not influence weight loss

Obesity has become a major public health problem, most commonly treated via dietary restriction to promote weight loss. Although leptin and thyroid hormones are involved in the regulation of energy balance, the role of these hormones after the stabilization of weight loss remains unclear. This study was designed to analyze the effect of thyroid hormone on sustained weight loss and leptin gene expression in obese animals after a loss of 5% to 10% of body weight. Thirty-day-old male Wistar rats were separated into 4 groups: control, obese, calorie restriction (CR), and calorie restriction with triiodothyronine administration (CRT). The obese group had increased weight and adiposity, leptin and insulin levels, and leptin gene expression. Dietary restriction in the CR group resulted in decreased body weight and adiposity, diminished leptin, and increased thyroid hormone receptor β expression. The CRT group, submitted to dietary restriction with concomitant administration of a physiologic triiodothyronine dose, had thyroid hormone receptor β expression at levels comparable with those observed in the control group and simultaneously increased leptin expression as compared with that in the CR group, suggesting that thyroid hormone modulates leptin expression under conditions of calorie restriction. Increased leptin expression in the CRT group did not result in increased circulating leptin or a statistically significant reduction in body weight during the treatment period. These data provide impetus for further study, as a longer treatment period may result in increased circulating leptin and, thus, further reduction in body weight during calorie restriction in an obesity model.     

Pancreatic polypeptide in obese children before and after weight loss

OBJECTIVE: Little is known concerning pancreatic polypeptide (PP) in weight loss and in childhood obesity. METHODS: Fasting PP, leptin and insulin concentrations were determined in 38 obese children and compared with 35 lean children of the same age, gender and pubertal stage. Furthermore, changes of PP concentrations over a 1-year period were analyzed in the obese children participating in a weight loss intervention program. RESULTS: Obese children had significantly (P<0.01) lower PP, and higher leptin and insulin levels compared to lean children. In multiple linear regression analysis, PP was significantly negatively correlated to body mass index (P<0.01), but not to leptin, insulin, age, gender and pubertal stage. Changes of PP did not significantly correlate to changes of insulin (r=0.07, P=0.343) and leptin (r=-0.02, P=0.459). The substantial weight loss in 17 children led to a significant (P<0.05) increase in PP and decrease in insulin and leptin. In the 21 children without substantial weight loss, there were no significant changes in PP, insulin and leptin. CONCLUSIONS: PP concentrations are decreased in obese children and independent of age, gender, pubertal stage, leptin and insulin. The decrease of PP in obese children normalized after weight loss. Therefore, low PP concentrations reflect the overweight status, rather than cause it.     

Targeted disruption of GPR7, the endogenous receptor for neuropeptides B and W,leads to metabolic defects and adult-onset obesity

Gold-thioglucose (GTG) induces lesions in the ventromedial nucleus of the hypothalamus, resulting in hyperphagia and obesity. To identify genes involved in the hypothalamic regulation of energy homeostasis, we used a screen for genes that are dysregulated in GTG-induced obese mice. We found that GPR7, the endogenous G protein-coupled receptor for the recently identified ligands neuropeptide B and neuropeptide W, was down-regulated in hypothalamus after GTG treatment. Here we show that male GPR7-/- mice develop an adult-onset obese phenotype that progressively worsens with age and was greatly exacerbated when animals are fed a high-fat diet. GPR7-/- male mice were hyperphagic and had decreased energy expenditure and locomotor activity. Plasma levels of glucose, leptin, and insulin were also elevated in these mice. GPR7-/- male mice had decreased hypothalamic neuropeptide Y RNA levels and increased proopiomelanocortin RNA levels, a set of effects opposite to those evident in ob/ob mice. Furthermore, ob/ob GPR7-/- and Ay/a GPR7-/- double mutant male mice had an increased body weight compared with normal ob/ob or Ay/a male mice, suggesting that the obesity of GPR7-/- mice is independent of leptin and melanocortin signaling. Female mice did not show any significant weight increase or associated metabolic defects. These data suggest a potential role for GPR7 and its endogenous ligands, neuropeptide B and neuropeptide W, in regulating energy homeostasis independent of leptin and melanocortin signaling in a sexually dimorphic manner.     

The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression

Metformin demonstrates anorectic effects in vivo and inhibits neuropeptide Y expression in cultured hypothalamic neurons. Here we investigated the mechanisms implicated in the modulation of feeding by metformin in animals rendered obese by long-term high-fat diet (diet-induced obesity [DIO]) and in animals resistant to obesity (diet resistant [DR]). Male Long-Evans rats were kept on normal chow feeding (controls) or on high-fat diet (DIO, DR) for 6 months. Afterward, rats were treated 14 days with metformin (75 mg/kg) or isotonic sodium chloride solution and killed. Energy efficiency, metabolic parameters, and gene expression were analyzed at the end of the high-fat diet period and after 14 days of metformin treatment. At the end of the high-fat diet period, despite higher leptin levels, DIO rats had higher levels of hypothalamic neuropeptide Y expression than DR or control rats, suggesting a central leptin resistance. In DIO but also in DR rats, metformin treatment induced significant reductions of food intake accompanied by decreases in body weight. Interestingly, the weight loss achieved by metformin was correlated with pretreatment plasma leptin levels. This effect was paralleled by a stimulation of the expression of the leptin receptor gene (ObRb) in the arcuate nucleus. These data identify the hypothalamic ObRb as a gene modulated after metformin treatment and suggest that the anorectic effects of the drug are potentially mediated via an increase in the central sensitivity to leptin. Thus, they provide a rationale for novel therapeutic approaches associating leptin and metformin in the treatment of obesity.     

Similar metabolic responses to calorie restriction in lean and obese Zucker rats

Calorie restriction (CR), which is thought to be largely dependent on the neuroendocrine system modulated by insulin/insulin-like growth factor-I (IGF-I) and leptin signaling, decreases morbidity and increases lifespan in many organisms. To elucidate whether insulin and leptin sensitivities are indispensable in the metabolic adaptation to CR, we investigated the effects of CR on obese Zucker (fa/fa) rats and lean control (+/+) rats. CR did not fully improve insulin resistance in (fa/fa) rats. Nonetheless, CR induced neuropeptide Y (NPY) expression in the hypothalamic arcuate nucleus and metabolism related gene expression changes in the liver in (fa/fa) rats and (+/+) rats. Up-regulation of NPY augmented plasma corticosterone levels and suppressed pituitary growth hormone (GH) expression, thereby modulating adipocytokine production to induce tissue-specific insulin sensitivity. Thus, central NPY activation via peripheral signaling might play a crucial role in the effects of CR, even in insulin resistant and leptin receptor deficient conditions.