肥胖及减重手术对PPARγ、瘦素、抵抗素、脂联素的影响及意义
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摘要
研究背景
减重手术或胃肠代谢手术可治愈或缓解2型糖尿病已被大量临床研究证实,但其机制尚未完全阐明。胰岛功能衰竭和胰岛素抵抗是2型糖尿病的两大特征,但相关机制研究绝大多数针对减重/代谢手术改善胰岛细胞功能展开,而对术后胰岛素抵抗改善机制的研究却很少。研究发现过氧化物酶体增殖物激活受体丫(peroxisome proliferator-activated receptor γ, PPARγ)不但是临床上噻唑烷二酮类胰岛素增敏剂的作用靶点,而且它还能调节瘦素、抵抗素、脂联素等与胰岛素抵抗关系密切的脂肪细胞因子的表达。肥胖可引起PPARγ、瘦素、抵抗素、脂联素的表达增高,造成胰岛素抵抗：反之,减重或代谢手术可能通过影响PPARγ、瘦素、抵抗素、脂联素水平,进而改善胰岛素抵抗,本研究分别从临床研究及动物实验对此进行探索。
第一部分临床研究肥胖对PPARγ、瘦素、抵抗素、脂联素的影响及其意义
目的研究肥胖患者PPARγ、瘦素、抵抗素、脂联素的表达变化并探讨其意义。
方法以2009.10-2011.2北京协和医院行腹腔镜可调节胃束带术的单纯肥胖患者为肥胖组,以同组医师同期完成常规胃肠手术的正常BMI患者为对照组,测量体重、身高,记录空腹血糖(FPG),甘油三酯(TG),总胆固醇(TC),低密度脂蛋白胆固醇(LDL-C),高密度脂蛋白胆固醇(HDL-C),收缩压(SBP)及舒张压(DBP),按照公式计算体质指数(BMI)、胰岛素抵抗指数(HOMA-IR)。术中留取血、皮下及内脏脂肪标本,ELISA法检测其中PPARγ、瘦素、抵抗素、脂联素表达水平,比较上述指标的组间差异,用Pearson相关分析研究肥胖组中各检测指标间的相关性。
结果肥胖组纳入病例16例(男6例,女10例),对照组纳入6例(男2例,女4例),两组患者年龄、身高无显著差异[(30.4±9.1)岁vs.(45.5±15.7)岁,P=0.066；(168.9±10.3)cmvs.(164.2±9.2)cm,P=0.388],除HDL-C显著降低外,肥胖组BMI、空腹血糖、血脂、血压较对照组显著增高：BMI[(46.5±8.5)kg/m2vs.(21.6±0.6)kg/m2,P=0.000],FPG[(6.3±1.8) mmol/L vs.(4.6±0.5) mmol/L, P=0.002], TG[(2.2±0.8) mmol/L vs.(0.8±0.3) mmol/L, P=0.000], TC[(5.3±1.1) mmol/L vs.(4.0±0.9) mmol/L, P=0.019], LDL-C[(3.5±0.9) mmol/L vs.(2.5±0.7) mmol/L, P=0.016], HDL-C[(0.9±0.2) mmol/L vs.(1.3±0.2) mmol/L, P=0.015], SBP[(133.3±14.8)mmHg vs.(107.0±13.2) mmHg, P=0.002], DBP[(89.6±11.8) mmHg vs.(69.2±4.9) mmHg, P=0.000].肥胖组与对照组相比：皮下、内脏脂肪PPARγ显著升高[(0.20±0.16) pg/ml vs.(0.06±0.02) pg/ml, P=0.044;(0.14±0.04) pg/ml vs.(0.09±0.02) pg/ml, P=0.004],皮下、内脏脂肪瘦素显著增高[(9.51±5.45) ng/ml vs.(2.55±0.78) ng/ml, P=0.000;(7.08±3.17) ng/ml vs.(2.60±0.24) ng/ml, P=0.000],皮下、内脏脂肪脂联素显著降低[(6.13±1.25) ng/ml vs.(16.5±2.0) ng/ml, P=0.000;(5.05±1.88) ng/ml vs.(60.00±23.34) ng/ml, P=0.006],皮下、内脏脂肪抵抗素无显著增加[(1.43±1.06) ng/ml vs.(0.77±0.06)ng/ml, P=0.319;(0.74±0.26)ng/ml vs.(0.55±0.19)ng/ml, P=0.199],肥胖组血胰岛素、HOMA-IR均高于正常范围[(17.4±5.0) uIU/ml>17.2uIU/m;(7.5±4.0) uIU/ml*mmol/L>4.5uIU/ml*mmol/L]。皮下脂肪中PPARγ与瘦素、抵抗素、脂联素显著正相关(r=0.997,P=0.000；r=1.0,P=0.000；r=0.995,P=0.000),内脏脂肪中PPARγ与瘦素、抵抗素、脂联素显著正相关(r=0.994,P=0.000；r=0.998,P=0.000；r=0.992,P=0.000),内脏脂肪中PPARγ、瘦素、抵抗素、脂联素均与TG显著负相关(r=-0.679,P=0.021；r=-0.644,P=0.032；r=-0.695,P=0.018；r=-0.643,P=0.033)),BMI、腰围与FPG显著正相关(r=0.696,P=0.017；r=0.661,P=0.027),HOMA-IR与FPG、HbA1C、血胰岛素显著正相关(r=0.937,P=0.000；r=0.768,P=0.016；r=0.881,P=0.000)。
结论肥胖患者PPARγ、瘦素表达增加,脂联素表达降低,可导致胰岛素抵抗。减重手术后体重显著下降,可能引起PPARγ、瘦素表达降低,脂联素表达升高,从而使胰岛素抵抗改善。
第二部分动物实验减重手术对肥胖大鼠PPARγ、瘦素、抵抗素、脂联素的影响及意义
目的研究减重手术对肥胖大鼠PPARγ、瘦素、抵抗素、脂联素的影响及意义。
方法以高脂饲料诱导建立肥胖大鼠模型,成模的肥胖大鼠行胃旁路术、袖状胃切除术或剖腹探查术,但肥胖对照组以及对照饲料喂养的正常对照组均不手术。手术前后定期测量大鼠体重、空腹血浆葡萄糖,术后4周用酶联免疫分析法检测大鼠胰岛素、过氧化物酶体增殖物激活受体y(PPARy)、瘦素(leptin)、抵抗素(resistin)、脂联素(adiponectin),用单因素方差分析比较各检测指标的组间差异,用Pearson相关分析考查它们之间的相关性。
结果高脂饲料喂养12周成功建立肥胖大鼠模型,建模组26只大鼠肥胖[(730.3+18.0)gvs.(555.9±55.8)g,P=0.000],成模率50%(26/52),分别行胃旁路术、袖状胃切除术或剖腹探查术：胃旁路术(n=8)组6只大鼠存活,其余2只分别于术后第4天、第8天死于胃肠吻合口瘘及空肠吻合口狭窄导致的不全肠梗阻；袖状胃切除术(n=7)组5只大鼠存活,其余2只分别于术后第2天、第7天死于胃流出道不全梗阻及残胃瘘；剖腹探查术(n=7)组7只大鼠均存活。术后1周：与肥胖对照组相比,胃旁路组、袖状胃切除组体重显著减轻[(684.7±36.2)g vs.(615.0±27.2)g,P=0.004；(684.7±36.2)gvs.(632.5±34.7)g,P=0.042],但胃旁路组较袖状胃切除组体重无显著减轻[(615.0±27.2)gvs.(632.5±34.7)g,P=0.294]；剖腹探查组体重也无显著减轻[(684.7±36.2)gvs.(649.4±36.0)g,P=0.199)。术后4周：胃旁路组、袖状胃切除组均较肥胖对照组体重持续显著减轻[(470.7±40.8)g vs.(698.2±20.8)g,P=0.000；(511.44-13.0)g vs.(698.2±20.8),P=0.000]；且胃旁路组较袖状胃切除组体重显著减轻[(470.7±40.8)gvs.(511.4±13.0)g,P=0.026],剖腹探查组较肥胖对照组体重仍无显著减轻[(667.6±38.9)gvs.(698.2±20.8)g,P=0.184]；与正常对照组相比,肥胖对照组大鼠空腹血糖[(5.3±0.4) mmol/L vs.(7.2±0.4) mmol/L, P=0.000]、血胰岛素[(1.1±0.3) ng/ml vs.(1.6±0.4) ng/ml, P=0.034]、胰岛素抵抗指数(6.4±0.5) uIU/ml*mmol/L vs.(12.7±0.9) ulU/ml*mmol/L,P=0.000]均显著增加；与肥胖对照组相比,胃旁路组、袖状胃切除组空腹血糖[(7.2±0.4) mmol/L vs.(5.9±0.6) mmol/L, P=0.003;(7.2±0.4) mmol/L vs.(4.7±0.4) mmol/L, P=0.000]、血胰岛素[(1.6±0.4)ng/mlvs.(0.8±0.6)ng/ml,P=0.038;(1.6±0.4) ng/ml vs.(0.9±0.5) ng/ml, P=0.041]、胰岛素抵抗指数[(12.7±0.9) uIU/ml*mmol/L vs (5.2±1.4) uIU/ml*mmol/L, P=0.000;(12.7±0.9) uIU/ml*mmol/L vs.(4.7±0.4) uIU/ml*mmol/L, P=0.000]均显著降低；与正常对照组相比,肥胖对照组大鼠皮下脂肪瘦素水平显著增加[(0.5±0.3) ng/ml vs.(6.8±3.9) ng/ml, P=0.000],内脏脂肪瘦素水平显著降低[(9.1±4.9) ng/ml vs.(3.0±2.0) ng/ml, P=0.041];与肥胖对照组相比,胃旁路组、袖状胃切除组减重手术后皮下脂肪瘦素水平均降低[(6.8±3.9) ng/ml vs.(0.3±0.2) ng/ml, P=0.000;(6.8±3.9) ng/ml vs.(4.6±1.9) ng/ml, P=0.231],内脏脂肪瘦素水平显著降低[(3.0±2.0) ng/ml vs(0.7±0.4) ng/ml, P=0.008;(3.0±2.0) ng/ml vs.(0.9±0.5) ng/ml, P=0.023];与正常对照组相比,肥胖对照组皮下脂肪抵抗素显著升高[(1.6±1.3) ng/ml vs.(3.5±1.4) ng/ml, P=0.041],内脏脂肪抵抗素显著降低[(15.1±11.5) ng/ml vs.(1.7±0.4) ng/ml, P=0.046];与肥胖对照组相比,胃旁路组皮下脂肪抵抗素显著降低[(3.5±1.4) ng/ml vs (1.7±0.7) ng/ml, P=0.012],袖状胃切除组皮下脂肪抵抗素无显著降低(3.5±1.4) ng/ml vs.(1.8±1.1) ng/ml,P=0.051],胃旁路组内脏抵抗素升高[(1.7±0.4) ng/ml vs.(2.2±0.3) ng/ml, P=0.034],袖状胃切除组内脏脂肪抵抗素无显著增高(1.7±0.4) ng/ml vs.(2.0±0.6) ng/ml,P=0.392]；与正常对照组相比,肥胖对照组皮下脂肪脂联素无素显著改变[(2.34±1.3)ng/ml vs.(2.1±1.9) ng/ml, P=0.833],内脏脂肪脂联素显著降低[(3.3±1.3) ng/ml vs.(1.1±0.6) ng/ml, P=0.010];与肥胖对照组相比,胃旁路组皮下脂肪脂联素无显著变化[(2.1±1.9) ng/ml vs (0.8±0.9) ng/ml, P=0.129],袖状胃切除组皮下脂肪抵抗素无显著降低(2.1±1.9) ng/ml vs.(2.3±1.6) ng/ml,P=0.856],胃旁路组内脏脂肪脂联素降低无显著降低[(1.1±0.6) ng/ml vs.(0.9±0.6) ng/ml, P=0.5981,袖状胃切除组内脏脂肪脂联素显著降低(1.1±0.6) ng/ml vs.(0.5±0.1) ng/ml, P=0.024];与正常对照组相比,肥胖对照组血瘦素显著升高[(0.3±0.1) ng/ml vs.(1.2±0.3) ng/ml,P=0.000],血抵抗素也显著升高(1.4±0.3) ng/ml vs.(14.4±5.3) ng/ml, P=0.000],血脂联素也显著升高(0.6±0.1) ng/ml vs.(17.2±1.2) ng/ml, P=0.000];与肥胖对照组相比,胃旁路组、袖状胃切除组血瘦素均显著降低[(1.2±0.3) ng/ml vs.(0.3±0.1) ng/ml, P=0.000;(1.2±0.3) ng/ml vs.(0.4±0.3) ng/ml, P=0.002],血抵抗素无显著改变[(14.4±5.3)ng/mlvs.(9.7±2.8)ng/ml,P=0.066;(14.4±5.3)ng/ml vs.(11.4±6.5) ng/ml, P=0.454],胃旁路组、袖状胃切除组血脂联素均显著降低[(17.2±1.2) ng/ml vs.(10.6±2.9) ng/ml, P=0.000;(17.2±1.2) ng/ml vs.(11.3±2.9) ng/ml, P=0.000];与正常对照组相比,肥胖对照组皮下脂肪PPARγ水平显著增加[(0.4±0.2) pg/ml vs.(1.6±0.4) pg/ml, P=0.000],内脏脂肪PPARγ水平显著降低[(1.4±0.5) pg/ml vs.(0.6±0.3) pg/ml, P=0.016];与肥胖对照组相比,胃旁路组、袖状胃切除组皮下脂肪PPARy均显著下降[(1.6±0.4) pg/ml vs.(0.3±0.1) pg/ml, P=0.000;(1.6±0.4) pg/ml vs.(0.5±0.2) pg/ml,P=0.000],胃旁路组、袖状胃切除组内脏脂肪PPARy无显著降低[(0.7±0.3) pg/ml vs.(0.6±0.3) pg/ml, P=0.598;(1.4±0.7) pg/ml vs.(0.6±0.3) pg/ml, P=0.061]。皮下脂肪组织PPARγ与体重显著正相关(r=0.731,P=0.049)；皮下脂肪PPARγ、皮下脂肪瘦素与血瘦素显著正相关(r=0.936,P=0.002；r=0.772,P=0.042)。
结论成功建立肥胖及减重手术大鼠模型,肥胖大鼠PPARγ、瘦素、抵抗素均显著升高,胰岛素抵抗增加；肥胖大鼠减重术后PPARγ及脂联素、瘦素降低,胰岛素抵抗也改善；减重/代谢手术可能通过降低PPARγ、瘦素改善胰岛素抵抗。
Background
Weight loss surgery or gastrointestinal metabolic surgery can cure or alleviate type2diabetes has been confirmed by a large number of clinical evidence. As we all known, exhaustion of pancreatic β cells and insulin resistance are the two features of type2diabetes mellitus, in which the latter existed in the occurrence and development of type2diabetes, and it preceded the former. But most mechanistic studies focus on improving function of β cells, while very few research aimed at mechanisms of insulin resistance ameliorated. Peroxisome proliferator-activated receptor y (PPARy), leptin, resistin, adiponectin and other adipocytokines closely relate with glucose and lipid metabolism, espicially insulin resistance, which are indicated in lots of basic and clinical researches, and PPARy is the effect target of clinical insulin-sensitizing agents. Obesity can increase PPARy, leptin and resistin expression, and decrease adiponectin, which all result in insulin resistance; then on the other hand, bariatric surgery and gastrointestinal metabolic surgeries might lead to weight loss, and levels of PPARy, leptin, resistin and adiponectin will be changed, thereby improving insulin resistance might be possible. So we explored it in animal experiments and clinical study.
Part I Clinical research Impact of obesity on PPARy, leptin, resistin and adiponectin
Objective To investigate the impact of obesity on PPARy, leptin, resistin and adiponectin.
Methods The study involved obese patients underwent laparoscopic adjustable gastric banding (obese group) or normal body mass index(BMI) individuals accepted routine gastrointestinal surgeries(control group) performed by one gastrointestinal surgeon team from Oct.2009to Feb.2011in Peking Union Medical College Hospital. With prior informed consent, body weight, height, waist circumference (WC), fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded, then BMI and homeostasis model assessment for insulin resistance (HOMA-IR) index were calculated by the formula, respectively. Samples of fasting blood, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were obtained, and levels of PPARy, leptin, resistin and adiponectin were assayed by enzyme-linked immunosorbent assay (ELISA) kits, then differences and correlations among PPARy, leptin, resistin, adiponectin and obesity related metabolic indicators were analyzed in obese group.
Results The obese group included16cases (6men and10women), while the control group involved6cases (2men and4women). Significantly differeces existed between the two groups in body weight[(133.2±27.4) kg vs.(58.5±6.6) kg, P=0.000], BMI[(46.5±8.5) kg/m2vs.(21.6±0.6) kg/m2, P=0.000], FPG[(6.3±1.8) mmol/L vs.(4.6±0.5) mmol/L, P=0.002], LDL-C[(3.5±0.9) mmol/L vs.(2.5±0.7) mmol/L, P=0.016], HDL-C[(0.9±0.2) mmol/L vs.(1.3±0.2) mmol/L, P=0.015], TG[(2.2±0.8) mmol/L vs.(0.8±0.3) mmol/L, P=0.000], TC[(5.3±1.1) mmol/L vs.(4.0±0.9) mmol/L, P=0.019], SBP[(133.3±14.8) mmHg vs.(107.0±13.2) mmHg, P=0.002] and DBP[(89.6±11.8) mmHg vs.(69.2±4.9) mmHg, P=0.000], but not age[(30.4±9.1) years vs.(45.5±15.7) years, P=0.066] or height [(168.9±10.3) cm vs.(164.2±9.2) cm, P=0.388]. In contrast to control group, subcutaneous and visceral PPARy[(0.20±0.16) pg/ml vs.(0.06±0.02) pg/ml, P=0.044;(0.14±0.04) pg/ml vs.(0.09±0.02) pg/ml, P=0.004]or leptin[(9.51±5.45) ng/ml vs.(2.55±0.78) ng/ml,P=0.000;(7.08±3.17) ng/ml vs.(2.60±0.24) ng/ml, P=0.000], serum insulin[(17.4±5.0) uIU/ml>17.2uIU/m] and HOMA-IR[(7.5±4.0) uIU/ml*mmol/L>4.5uIU/ml*mmol/L] elevated, subcutaneous and visceral adiponectin[(16.5±2.0)ng/ml vs.(6.13±1.25)ng/ml,P=0.000;(60.00±23.34) ng/ml vs.(5.05±1.88) ng/ml, P=0.006] reduced, while resistin did not change significantly[(1.43±1.06) ng/ml vs.(0.77±0.06) ng/ml, P=0.319;(0.74±0.26) ng/ml vs.(0.55±0.19) ng/ml,P=0.199] in obese group. Within the obese group, PPARy positively correlated with leptin (r=0.997, P=0.000), resistin (r=1.0, P=0.000) and adiponectin(r=0.995, P=0.000) in SAT or VAT (r=0.994, P=0.000; r=0.998, P=0.000; r=0.992, P=0.000). PPARy, leptin, resistin and adiponectin were negatively correlated with TG in VAT(r=-0.679, P=0.021; r=-0.644, P=0.032; r=-0.695, P=0.018; r=-0.643, P=0.033). Either BMI or WC positively related with FPG (r=0.696,P=0.017; r=0.661, P=0.027). While FPG, HbA1C and serum insulin positively correlated with HOMA-IR (r=0.937, P=0.000; r=0.768, P=0.016; r=0.881, P=0.000)。
Conclusions In obese patients, PPARy and leptin elevated, adiponectin decreased, which all could result in insulin resistance. On the contrary, bariatric surgery or gastrointestinal surgeries can lead to significant weight loss, which might reduce PPARy and leptin, and increase adiponectin, then insulin resistance might be improved.
Part Ⅱ Investigation in rats Impact of bariatric surgeries on PPARy, leptin, resistin and adiponectin in obese rats
Objective To study the impact of weight loss surgery on PPARy, leptin, resistin and adiponectin in obese rats.
Methods Obese rodent model was established by high fat diet, then four groups were divided randomly according to body weight, then Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or exploratory laparotomy (EL) were performed respectively, while both obesity control (OC) group and normal control (NC) group were continued to feed without surgeries. Body weight and fasting plasma glucose (FPG) were detected regularly before and after the operation. Levels of PPARy, leptin, resistin, adiponectin and insulin in fasting blood, subcutaneous or visceral adipose tissue were determined by enzyme-linked immunosorbent assay (EILISA) kit4weeks after the procedures. Correlation of PPARy, leptin, resistin, adiponectin and obesity related metabolic indicators were analyzed.
Results Given high fat diet to rats for12weeks,26(26/52) obese rats were obtained[(730.3±18.0) g vs.(555.9±55.8)g, P=0.000]. In RYGB group (n=8),6rats survived postoperative4weeks, while1rat died for gastrointestinal fistula at the4th postoperative day, and the other rat died due to jejunal incomplete obstruction resulted by anastomotic stenosis at the8th postoperative day. In SG group (n=7),5rats were alive4weeks postoperative, while1rat died due to obstruction of outflow tract in stomach at the3th postoperative day, and the other one died for residual gastric fistula1week after surgery. All7rats in EL group (n=7) survived to4weeks. Compared with OC group(n=4), both RYGB group and SG group got significantly weight loss1week after surgery[(684.7±36.2)g vs.(615.0±27.2) g, P=0.004;(684.7±36.2) g vs.(632.5±34.7) g, P=0.042], and RYGB group reduced more but not significant weight than SG group[(615.0±27.2) g vs.(632.5±34.7) g, P=0.294]. EL group weighted less but not significant than OC group[(684.7±36.2) g vs.(649.4±36.0) g, P=0.199]. No significant difference in body weight between EL group and OC group at4weeks after surgery[(667.6±38.9) g vs.(698.2±20.8) g, P=0.184], while both RYGB group and SG group gained sustain weight loss[(470.7±40.8) g vs.(698.2±20.8) g, P=0.000;(511.4±13.0) g vs.(698.2±20.8), P=0.000], and RYGB group decreased much more than SG group[(470.7±40.8) g vs.(511.4±13.0) g,P=0.026]. Compared with NC group, FPG, serum insulin and homeostasis model assessment for insulin resistance (HOMA-IR) index increased significantly in OC group([(5.3±0.4) mmol/L vs.(7.2±0.4) mmol/L, P=0.000;(1.1±0.3) ng/ml vs.(1.6±0.4) ng/ml, P=0.034;(6.4±0.5) uIU/ml*mmol/L vs.(12.7±0.9) uIU/ml*mmol/L, P=0.000], and they all reduced significantly either in RYGBgroup[(7.2±0.4) mmol/L vs.(5.9±0.6) mmol/L, P=0.003;(1.6±0.4) ng/ml vs.(0.8±0.6)ng/ml,P=0.038;(12.7±0.9)uIU/ml*mmol/L vs(5.2±1.4)uIU/ml*mmol/L, P=0.000] or SG group[(7.2±0.4) mmol/L vs.(4.7±0.4) mmol/L, P=0.000;(1.6±0.4) ng/ml vs.(0.9±0.5) ng/ml, P=0.041;(12.7±0.9) uIU/ml*mmol/L vs.(4.7±0.4) ulU/ml*mmol/L, P=0.000]4weeks postoperative. Compared with NC group, subcutaneous leptin increased significantly in OC group[(0.5±0.3) ng/ml vs.(6.8±3.9) ng/ml, P=0.000], while visceral leptin reduced[(9.1±4.9) ng/ml vs.(3.0±2.0) ng/ml, P=0.041]. In contrast to OC group, subcutaneous leptin decreased in RYGB group[(6.8±3.9) ng/ml vs.(0.3±0.2) ng/ml, P=0.000] or SG group[(6.8±3.9) ng/ml vs.(4.6±1.9) ng/ml, P=0.231], and it's the same for visceral leptin[(3.0±2.0) ng/ml vs.(0.7±0.4) ng/ml, P=0.008;(3.0±2.0) ng/ml vs.(0.9±0.5) ng/ml, P=0.023]. Compared with NC group, subcutaneous resistin increased [(1.6±1.3) ng/ml vs.(3.5±1.4) ng/ml, P=0.041] while visceral leptin reduced[(15.1±11.5) ng/ml vs.(1.7±0.4) ng/ml, P=0.046] in OC group. In contrast to OC group, subcutaneous resistin decreased and visceral resistin elevated in RYGB group[(3.5±1.4)ng/ml vs(.1.7±0.7)ng/ml, P=0.012;(3.5±1.4) ng/ml vs.(1.8±1.1) ng/ml, P=0.051]; subcutaneous resistin did not decreased signicantly [(3.5±1.4) ng/ml vs.(1.8±1.1) ng/ml, P=0.051] while visceral resistin elevated [(1.7±0.4) ng/ml vs.(2.2±0.3) ng/ml, P=0.034]in SG group. Compared with NC group, subcutaneous adiponectin did not change significantly in OC group[(2.3±1.3) ng/ml vs.(2.1±1.9) ng/ml, P=0.833], while visceral adiponectin reduced[(3.3±1.3) ng/ml vs.(1.1±0.6) ng/ml, P=0.010]. In contrast to OC group, subcutaneous adiponectin did not change greatly in RYGB group[(2.1±1.9) ng/ml vs.(0.8±0.9) ng/ml, P=0.129]or SG group[(2.1±1.9) ng/ml vs.(2.3±1.69) ng/ml, P=0.856], while visceral adiponectin reduced[(1.1±0.6) ng/ml vs.(0.9±0.6) ng/ml, P=0.598;(1.1±0.6) ng/ml vs.(0.5±0.1) ng/ml, P=0.024]. Compared with NC group, leptin, resistin and adiponectin increased in circulation of OC group[(0.3±0.1) ng/ml vs.(1.2±0.3) ng/ml, P=0.000;(1.4±0.3) ng/ml vs.(14.4±5.3) ng/ml, P=0.000;(0.6±0.1) ng/ml vs.(17.2±1.2) ng/ml, P=0.000]. In contrast to OC group, serum leptin and adiponectin decreased in RYGB group[(1.2±0.3) ng/ml vs.(0.3±0.1) ng/ml, P=0.000;(17.2±1.2) ng/ml vs.(10.6±2.9) ng/ml,P=0.000] and SG group[(1.2±0.3)ng/ml vs.(0.4±0.3)ng/ml, P=0.002;(17.2±1.2) ng/ml vs.(11.3±2.9) ng/ml, P=0.000], while serum resistin did not reduced significantly in RYGB group[(14.4±5.3) ng/ml vs.(9.7±2.8) ng/ml, P=0.066] and SG group[(14.4±5.3) ng/ml vs.(11.4±6.5) ng/ml, P=0.454]. Compared with NC group, subcutaneous PPARy increased in OC group[(0.4±0.2) pg/ml vs.(1.6±0.4) pg/ml, P=0.000], while visceral PPARy decreased[(1.4±0.5)pg/ml vs.(0.6±0.3)pg/ml, P=0.016]. In contrast to OC group, subcutaneous PPARy decreased in RYGB group[(1.6±0.4) pg/ml vs.(0.3±0.1) pg/ml, P=0.000] and SG group[(1.6±0.4) pg/ml vs.(0.5±0.2) pg/ml, P=0.000], while visceral PPARy did not decreased significantly in RYGB group[(0.7±0.3) pg/ml vs.(0.6±0.3) pg/ml, P=0.598] or in SG group[(1.4±0.7) pg/ml vs.(0.6±0.3) pg/ml, P=0.061]. In obese rats, subcutaneous PPARy positively correlated with body weight (r=0.731, P=0.049), while subcutaneous PPARy and leptin positively related with serum leptin (r=0.936, P=0.002; r=0.772, P=0.042).
Conclusions Both obese rodent model and bariatric surgical models were established successfully one after another. PPARy, leptin or resistin elevated in circulation of obese rats, and so did HOMA-IR. The elevated PPARy and leptin decreased after weight loss surgeries, and HOMA-IR also reduced. So it's possible that weight loss surgery or metabolic surgery improve insulin resistance through decreased PPARy and leptin.
减重手术或胃肠代谢手术可治愈或缓解2型糖尿病已被大量临床研究证实,但其机制尚未完全阐明。胰岛功能衰竭和胰岛素抵抗是2型糖尿病的两大特征,但相关机制研究绝大多数针对减重/代谢手术改善胰岛细胞功能展开,而对术后胰岛素抵抗改善机制的研究却很少。研究发现过氧化物酶体增殖物激活受体丫(peroxisome proliferator-activated receptor γ, PPARγ)不但是临床上噻唑烷二酮类胰岛素增敏剂的作用靶点,而且它还能调节瘦素、抵抗素、脂联素等与胰岛素抵抗关系密切的脂肪细胞因子的表达。肥胖可引起PPARγ、瘦素、抵抗素、脂联素的表达增高,造成胰岛素抵抗：反之,减重或代谢手术可能通过影响PPARγ、瘦素、抵抗素、脂联素水平,进而改善胰岛素抵抗,本研究分别从临床研究及动物实验对此进行探索。
第一部分临床研究肥胖对PPARγ、瘦素、抵抗素、脂联素的影响及其意义
目的研究肥胖患者PPARγ、瘦素、抵抗素、脂联素的表达变化并探讨其意义。
方法以2009.10-2011.2北京协和医院行腹腔镜可调节胃束带术的单纯肥胖患者为肥胖组,以同组医师同期完成常规胃肠手术的正常BMI患者为对照组,测量体重、身高,记录空腹血糖(FPG),甘油三酯(TG),总胆固醇(TC),低密度脂蛋白胆固醇(LDL-C),高密度脂蛋白胆固醇(HDL-C),收缩压(SBP)及舒张压(DBP),按照公式计算体质指数(BMI)、胰岛素抵抗指数(HOMA-IR)。术中留取血、皮下及内脏脂肪标本,ELISA法检测其中PPARγ、瘦素、抵抗素、脂联素表达水平,比较上述指标的组间差异,用Pearson相关分析研究肥胖组中各检测指标间的相关性。
结果肥胖组纳入病例16例(男6例,女10例),对照组纳入6例(男2例,女4例),两组患者年龄、身高无显著差异[(30.4±9.1)岁vs.(45.5±15.7)岁,P=0.066；(168.9±10.3)cmvs.(164.2±9.2)cm,P=0.388],除HDL-C显著降低外,肥胖组BMI、空腹血糖、血脂、血压较对照组显著增高：BMI[(46.5±8.5)kg/m2vs.(21.6±0.6)kg/m2,P=0.000],FPG[(6.3±1.8) mmol/L vs.(4.6±0.5) mmol/L, P=0.002], TG[(2.2±0.8) mmol/L vs.(0.8±0.3) mmol/L, P=0.000], TC[(5.3±1.1) mmol/L vs.(4.0±0.9) mmol/L, P=0.019], LDL-C[(3.5±0.9) mmol/L vs.(2.5±0.7) mmol/L, P=0.016], HDL-C[(0.9±0.2) mmol/L vs.(1.3±0.2) mmol/L, P=0.015], SBP[(133.3±14.8)mmHg vs.(107.0±13.2) mmHg, P=0.002], DBP[(89.6±11.8) mmHg vs.(69.2±4.9) mmHg, P=0.000].肥胖组与对照组相比：皮下、内脏脂肪PPARγ显著升高[(0.20±0.16) pg/ml vs.(0.06±0.02) pg/ml, P=0.044;(0.14±0.04) pg/ml vs.(0.09±0.02) pg/ml, P=0.004],皮下、内脏脂肪瘦素显著增高[(9.51±5.45) ng/ml vs.(2.55±0.78) ng/ml, P=0.000;(7.08±3.17) ng/ml vs.(2.60±0.24) ng/ml, P=0.000],皮下、内脏脂肪脂联素显著降低[(6.13±1.25) ng/ml vs.(16.5±2.0) ng/ml, P=0.000;(5.05±1.88) ng/ml vs.(60.00±23.34) ng/ml, P=0.006],皮下、内脏脂肪抵抗素无显著增加[(1.43±1.06) ng/ml vs.(0.77±0.06)ng/ml, P=0.319;(0.74±0.26)ng/ml vs.(0.55±0.19)ng/ml, P=0.199],肥胖组血胰岛素、HOMA-IR均高于正常范围[(17.4±5.0) uIU/ml>17.2uIU/m;(7.5±4.0) uIU/ml*mmol/L>4.5uIU/ml*mmol/L]。皮下脂肪中PPARγ与瘦素、抵抗素、脂联素显著正相关(r=0.997,P=0.000；r=1.0,P=0.000；r=0.995,P=0.000),内脏脂肪中PPARγ与瘦素、抵抗素、脂联素显著正相关(r=0.994,P=0.000；r=0.998,P=0.000；r=0.992,P=0.000),内脏脂肪中PPARγ、瘦素、抵抗素、脂联素均与TG显著负相关(r=-0.679,P=0.021；r=-0.644,P=0.032；r=-0.695,P=0.018；r=-0.643,P=0.033)),BMI、腰围与FPG显著正相关(r=0.696,P=0.017；r=0.661,P=0.027),HOMA-IR与FPG、HbA1C、血胰岛素显著正相关(r=0.937,P=0.000；r=0.768,P=0.016；r=0.881,P=0.000)。
结论肥胖患者PPARγ、瘦素表达增加,脂联素表达降低,可导致胰岛素抵抗。减重手术后体重显著下降,可能引起PPARγ、瘦素表达降低,脂联素表达升高,从而使胰岛素抵抗改善。
第二部分动物实验减重手术对肥胖大鼠PPARγ、瘦素、抵抗素、脂联素的影响及意义
目的研究减重手术对肥胖大鼠PPARγ、瘦素、抵抗素、脂联素的影响及意义。
方法以高脂饲料诱导建立肥胖大鼠模型,成模的肥胖大鼠行胃旁路术、袖状胃切除术或剖腹探查术,但肥胖对照组以及对照饲料喂养的正常对照组均不手术。手术前后定期测量大鼠体重、空腹血浆葡萄糖,术后4周用酶联免疫分析法检测大鼠胰岛素、过氧化物酶体增殖物激活受体y(PPARy)、瘦素(leptin)、抵抗素(resistin)、脂联素(adiponectin),用单因素方差分析比较各检测指标的组间差异,用Pearson相关分析考查它们之间的相关性。
结果高脂饲料喂养12周成功建立肥胖大鼠模型,建模组26只大鼠肥胖[(730.3+18.0)gvs.(555.9±55.8)g,P=0.000],成模率50%(26/52),分别行胃旁路术、袖状胃切除术或剖腹探查术：胃旁路术(n=8)组6只大鼠存活,其余2只分别于术后第4天、第8天死于胃肠吻合口瘘及空肠吻合口狭窄导致的不全肠梗阻；袖状胃切除术(n=7)组5只大鼠存活,其余2只分别于术后第2天、第7天死于胃流出道不全梗阻及残胃瘘；剖腹探查术(n=7)组7只大鼠均存活。术后1周：与肥胖对照组相比,胃旁路组、袖状胃切除组体重显著减轻[(684.7±36.2)g vs.(615.0±27.2)g,P=0.004；(684.7±36.2)gvs.(632.5±34.7)g,P=0.042],但胃旁路组较袖状胃切除组体重无显著减轻[(615.0±27.2)gvs.(632.5±34.7)g,P=0.294]；剖腹探查组体重也无显著减轻[(684.7±36.2)gvs.(649.4±36.0)g,P=0.199)。术后4周：胃旁路组、袖状胃切除组均较肥胖对照组体重持续显著减轻[(470.7±40.8)g vs.(698.2±20.8)g,P=0.000；(511.44-13.0)g vs.(698.2±20.8),P=0.000]；且胃旁路组较袖状胃切除组体重显著减轻[(470.7±40.8)gvs.(511.4±13.0)g,P=0.026],剖腹探查组较肥胖对照组体重仍无显著减轻[(667.6±38.9)gvs.(698.2±20.8)g,P=0.184]；与正常对照组相比,肥胖对照组大鼠空腹血糖[(5.3±0.4) mmol/L vs.(7.2±0.4) mmol/L, P=0.000]、血胰岛素[(1.1±0.3) ng/ml vs.(1.6±0.4) ng/ml, P=0.034]、胰岛素抵抗指数(6.4±0.5) uIU/ml*mmol/L vs.(12.7±0.9) ulU/ml*mmol/L,P=0.000]均显著增加；与肥胖对照组相比,胃旁路组、袖状胃切除组空腹血糖[(7.2±0.4) mmol/L vs.(5.9±0.6) mmol/L, P=0.003;(7.2±0.4) mmol/L vs.(4.7±0.4) mmol/L, P=0.000]、血胰岛素[(1.6±0.4)ng/mlvs.(0.8±0.6)ng/ml,P=0.038;(1.6±0.4) ng/ml vs.(0.9±0.5) ng/ml, P=0.041]、胰岛素抵抗指数[(12.7±0.9) uIU/ml*mmol/L vs (5.2±1.4) uIU/ml*mmol/L, P=0.000;(12.7±0.9) uIU/ml*mmol/L vs.(4.7±0.4) uIU/ml*mmol/L, P=0.000]均显著降低；与正常对照组相比,肥胖对照组大鼠皮下脂肪瘦素水平显著增加[(0.5±0.3) ng/ml vs.(6.8±3.9) ng/ml, P=0.000],内脏脂肪瘦素水平显著降低[(9.1±4.9) ng/ml vs.(3.0±2.0) ng/ml, P=0.041];与肥胖对照组相比,胃旁路组、袖状胃切除组减重手术后皮下脂肪瘦素水平均降低[(6.8±3.9) ng/ml vs.(0.3±0.2) ng/ml, P=0.000;(6.8±3.9) ng/ml vs.(4.6±1.9) ng/ml, P=0.231],内脏脂肪瘦素水平显著降低[(3.0±2.0) ng/ml vs(0.7±0.4) ng/ml, P=0.008;(3.0±2.0) ng/ml vs.(0.9±0.5) ng/ml, P=0.023];与正常对照组相比,肥胖对照组皮下脂肪抵抗素显著升高[(1.6±1.3) ng/ml vs.(3.5±1.4) ng/ml, P=0.041],内脏脂肪抵抗素显著降低[(15.1±11.5) ng/ml vs.(1.7±0.4) ng/ml, P=0.046];与肥胖对照组相比,胃旁路组皮下脂肪抵抗素显著降低[(3.5±1.4) ng/ml vs (1.7±0.7) ng/ml, P=0.012],袖状胃切除组皮下脂肪抵抗素无显著降低(3.5±1.4) ng/ml vs.(1.8±1.1) ng/ml,P=0.051],胃旁路组内脏抵抗素升高[(1.7±0.4) ng/ml vs.(2.2±0.3) ng/ml, P=0.034],袖状胃切除组内脏脂肪抵抗素无显著增高(1.7±0.4) ng/ml vs.(2.0±0.6) ng/ml,P=0.392]；与正常对照组相比,肥胖对照组皮下脂肪脂联素无素显著改变[(2.34±1.3)ng/ml vs.(2.1±1.9) ng/ml, P=0.833],内脏脂肪脂联素显著降低[(3.3±1.3) ng/ml vs.(1.1±0.6) ng/ml, P=0.010];与肥胖对照组相比,胃旁路组皮下脂肪脂联素无显著变化[(2.1±1.9) ng/ml vs (0.8±0.9) ng/ml, P=0.129],袖状胃切除组皮下脂肪抵抗素无显著降低(2.1±1.9) ng/ml vs.(2.3±1.6) ng/ml,P=0.856],胃旁路组内脏脂肪脂联素降低无显著降低[(1.1±0.6) ng/ml vs.(0.9±0.6) ng/ml, P=0.5981,袖状胃切除组内脏脂肪脂联素显著降低(1.1±0.6) ng/ml vs.(0.5±0.1) ng/ml, P=0.024];与正常对照组相比,肥胖对照组血瘦素显著升高[(0.3±0.1) ng/ml vs.(1.2±0.3) ng/ml,P=0.000],血抵抗素也显著升高(1.4±0.3) ng/ml vs.(14.4±5.3) ng/ml, P=0.000],血脂联素也显著升高(0.6±0.1) ng/ml vs.(17.2±1.2) ng/ml, P=0.000];与肥胖对照组相比,胃旁路组、袖状胃切除组血瘦素均显著降低[(1.2±0.3) ng/ml vs.(0.3±0.1) ng/ml, P=0.000;(1.2±0.3) ng/ml vs.(0.4±0.3) ng/ml, P=0.002],血抵抗素无显著改变[(14.4±5.3)ng/mlvs.(9.7±2.8)ng/ml,P=0.066;(14.4±5.3)ng/ml vs.(11.4±6.5) ng/ml, P=0.454],胃旁路组、袖状胃切除组血脂联素均显著降低[(17.2±1.2) ng/ml vs.(10.6±2.9) ng/ml, P=0.000;(17.2±1.2) ng/ml vs.(11.3±2.9) ng/ml, P=0.000];与正常对照组相比,肥胖对照组皮下脂肪PPARγ水平显著增加[(0.4±0.2) pg/ml vs.(1.6±0.4) pg/ml, P=0.000],内脏脂肪PPARγ水平显著降低[(1.4±0.5) pg/ml vs.(0.6±0.3) pg/ml, P=0.016];与肥胖对照组相比,胃旁路组、袖状胃切除组皮下脂肪PPARy均显著下降[(1.6±0.4) pg/ml vs.(0.3±0.1) pg/ml, P=0.000;(1.6±0.4) pg/ml vs.(0.5±0.2) pg/ml,P=0.000],胃旁路组、袖状胃切除组内脏脂肪PPARy无显著降低[(0.7±0.3) pg/ml vs.(0.6±0.3) pg/ml, P=0.598;(1.4±0.7) pg/ml vs.(0.6±0.3) pg/ml, P=0.061]。皮下脂肪组织PPARγ与体重显著正相关(r=0.731,P=0.049)；皮下脂肪PPARγ、皮下脂肪瘦素与血瘦素显著正相关(r=0.936,P=0.002；r=0.772,P=0.042)。
结论成功建立肥胖及减重手术大鼠模型,肥胖大鼠PPARγ、瘦素、抵抗素均显著升高,胰岛素抵抗增加；肥胖大鼠减重术后PPARγ及脂联素、瘦素降低,胰岛素抵抗也改善；减重/代谢手术可能通过降低PPARγ、瘦素改善胰岛素抵抗。
Background
Weight loss surgery or gastrointestinal metabolic surgery can cure or alleviate type2diabetes has been confirmed by a large number of clinical evidence. As we all known, exhaustion of pancreatic β cells and insulin resistance are the two features of type2diabetes mellitus, in which the latter existed in the occurrence and development of type2diabetes, and it preceded the former. But most mechanistic studies focus on improving function of β cells, while very few research aimed at mechanisms of insulin resistance ameliorated. Peroxisome proliferator-activated receptor y (PPARy), leptin, resistin, adiponectin and other adipocytokines closely relate with glucose and lipid metabolism, espicially insulin resistance, which are indicated in lots of basic and clinical researches, and PPARy is the effect target of clinical insulin-sensitizing agents. Obesity can increase PPARy, leptin and resistin expression, and decrease adiponectin, which all result in insulin resistance; then on the other hand, bariatric surgery and gastrointestinal metabolic surgeries might lead to weight loss, and levels of PPARy, leptin, resistin and adiponectin will be changed, thereby improving insulin resistance might be possible. So we explored it in animal experiments and clinical study.
Part I Clinical research Impact of obesity on PPARy, leptin, resistin and adiponectin
Objective To investigate the impact of obesity on PPARy, leptin, resistin and adiponectin.
Methods The study involved obese patients underwent laparoscopic adjustable gastric banding (obese group) or normal body mass index(BMI) individuals accepted routine gastrointestinal surgeries(control group) performed by one gastrointestinal surgeon team from Oct.2009to Feb.2011in Peking Union Medical College Hospital. With prior informed consent, body weight, height, waist circumference (WC), fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded, then BMI and homeostasis model assessment for insulin resistance (HOMA-IR) index were calculated by the formula, respectively. Samples of fasting blood, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were obtained, and levels of PPARy, leptin, resistin and adiponectin were assayed by enzyme-linked immunosorbent assay (ELISA) kits, then differences and correlations among PPARy, leptin, resistin, adiponectin and obesity related metabolic indicators were analyzed in obese group.
Results The obese group included16cases (6men and10women), while the control group involved6cases (2men and4women). Significantly differeces existed between the two groups in body weight[(133.2±27.4) kg vs.(58.5±6.6) kg, P=0.000], BMI[(46.5±8.5) kg/m2vs.(21.6±0.6) kg/m2, P=0.000], FPG[(6.3±1.8) mmol/L vs.(4.6±0.5) mmol/L, P=0.002], LDL-C[(3.5±0.9) mmol/L vs.(2.5±0.7) mmol/L, P=0.016], HDL-C[(0.9±0.2) mmol/L vs.(1.3±0.2) mmol/L, P=0.015], TG[(2.2±0.8) mmol/L vs.(0.8±0.3) mmol/L, P=0.000], TC[(5.3±1.1) mmol/L vs.(4.0±0.9) mmol/L, P=0.019], SBP[(133.3±14.8) mmHg vs.(107.0±13.2) mmHg, P=0.002] and DBP[(89.6±11.8) mmHg vs.(69.2±4.9) mmHg, P=0.000], but not age[(30.4±9.1) years vs.(45.5±15.7) years, P=0.066] or height [(168.9±10.3) cm vs.(164.2±9.2) cm, P=0.388]. In contrast to control group, subcutaneous and visceral PPARy[(0.20±0.16) pg/ml vs.(0.06±0.02) pg/ml, P=0.044;(0.14±0.04) pg/ml vs.(0.09±0.02) pg/ml, P=0.004]or leptin[(9.51±5.45) ng/ml vs.(2.55±0.78) ng/ml,P=0.000;(7.08±3.17) ng/ml vs.(2.60±0.24) ng/ml, P=0.000], serum insulin[(17.4±5.0) uIU/ml>17.2uIU/m] and HOMA-IR[(7.5±4.0) uIU/ml*mmol/L>4.5uIU/ml*mmol/L] elevated, subcutaneous and visceral adiponectin[(16.5±2.0)ng/ml vs.(6.13±1.25)ng/ml,P=0.000;(60.00±23.34) ng/ml vs.(5.05±1.88) ng/ml, P=0.006] reduced, while resistin did not change significantly[(1.43±1.06) ng/ml vs.(0.77±0.06) ng/ml, P=0.319;(0.74±0.26) ng/ml vs.(0.55±0.19) ng/ml,P=0.199] in obese group. Within the obese group, PPARy positively correlated with leptin (r=0.997, P=0.000), resistin (r=1.0, P=0.000) and adiponectin(r=0.995, P=0.000) in SAT or VAT (r=0.994, P=0.000; r=0.998, P=0.000; r=0.992, P=0.000). PPARy, leptin, resistin and adiponectin were negatively correlated with TG in VAT(r=-0.679, P=0.021; r=-0.644, P=0.032; r=-0.695, P=0.018; r=-0.643, P=0.033). Either BMI or WC positively related with FPG (r=0.696,P=0.017; r=0.661, P=0.027). While FPG, HbA1C and serum insulin positively correlated with HOMA-IR (r=0.937, P=0.000; r=0.768, P=0.016; r=0.881, P=0.000)。
Conclusions In obese patients, PPARy and leptin elevated, adiponectin decreased, which all could result in insulin resistance. On the contrary, bariatric surgery or gastrointestinal surgeries can lead to significant weight loss, which might reduce PPARy and leptin, and increase adiponectin, then insulin resistance might be improved.
Part Ⅱ Investigation in rats Impact of bariatric surgeries on PPARy, leptin, resistin and adiponectin in obese rats
Objective To study the impact of weight loss surgery on PPARy, leptin, resistin and adiponectin in obese rats.
Methods Obese rodent model was established by high fat diet, then four groups were divided randomly according to body weight, then Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) or exploratory laparotomy (EL) were performed respectively, while both obesity control (OC) group and normal control (NC) group were continued to feed without surgeries. Body weight and fasting plasma glucose (FPG) were detected regularly before and after the operation. Levels of PPARy, leptin, resistin, adiponectin and insulin in fasting blood, subcutaneous or visceral adipose tissue were determined by enzyme-linked immunosorbent assay (EILISA) kit4weeks after the procedures. Correlation of PPARy, leptin, resistin, adiponectin and obesity related metabolic indicators were analyzed.
Results Given high fat diet to rats for12weeks,26(26/52) obese rats were obtained[(730.3±18.0) g vs.(555.9±55.8)g, P=0.000]. In RYGB group (n=8),6rats survived postoperative4weeks, while1rat died for gastrointestinal fistula at the4th postoperative day, and the other rat died due to jejunal incomplete obstruction resulted by anastomotic stenosis at the8th postoperative day. In SG group (n=7),5rats were alive4weeks postoperative, while1rat died due to obstruction of outflow tract in stomach at the3th postoperative day, and the other one died for residual gastric fistula1week after surgery. All7rats in EL group (n=7) survived to4weeks. Compared with OC group(n=4), both RYGB group and SG group got significantly weight loss1week after surgery[(684.7±36.2)g vs.(615.0±27.2) g, P=0.004;(684.7±36.2) g vs.(632.5±34.7) g, P=0.042], and RYGB group reduced more but not significant weight than SG group[(615.0±27.2) g vs.(632.5±34.7) g, P=0.294]. EL group weighted less but not significant than OC group[(684.7±36.2) g vs.(649.4±36.0) g, P=0.199]. No significant difference in body weight between EL group and OC group at4weeks after surgery[(667.6±38.9) g vs.(698.2±20.8) g, P=0.184], while both RYGB group and SG group gained sustain weight loss[(470.7±40.8) g vs.(698.2±20.8) g, P=0.000;(511.4±13.0) g vs.(698.2±20.8), P=0.000], and RYGB group decreased much more than SG group[(470.7±40.8) g vs.(511.4±13.0) g,P=0.026]. Compared with NC group, FPG, serum insulin and homeostasis model assessment for insulin resistance (HOMA-IR) index increased significantly in OC group([(5.3±0.4) mmol/L vs.(7.2±0.4) mmol/L, P=0.000;(1.1±0.3) ng/ml vs.(1.6±0.4) ng/ml, P=0.034;(6.4±0.5) uIU/ml*mmol/L vs.(12.7±0.9) uIU/ml*mmol/L, P=0.000], and they all reduced significantly either in RYGBgroup[(7.2±0.4) mmol/L vs.(5.9±0.6) mmol/L, P=0.003;(1.6±0.4) ng/ml vs.(0.8±0.6)ng/ml,P=0.038;(12.7±0.9)uIU/ml*mmol/L vs(5.2±1.4)uIU/ml*mmol/L, P=0.000] or SG group[(7.2±0.4) mmol/L vs.(4.7±0.4) mmol/L, P=0.000;(1.6±0.4) ng/ml vs.(0.9±0.5) ng/ml, P=0.041;(12.7±0.9) uIU/ml*mmol/L vs.(4.7±0.4) ulU/ml*mmol/L, P=0.000]4weeks postoperative. Compared with NC group, subcutaneous leptin increased significantly in OC group[(0.5±0.3) ng/ml vs.(6.8±3.9) ng/ml, P=0.000], while visceral leptin reduced[(9.1±4.9) ng/ml vs.(3.0±2.0) ng/ml, P=0.041]. In contrast to OC group, subcutaneous leptin decreased in RYGB group[(6.8±3.9) ng/ml vs.(0.3±0.2) ng/ml, P=0.000] or SG group[(6.8±3.9) ng/ml vs.(4.6±1.9) ng/ml, P=0.231], and it's the same for visceral leptin[(3.0±2.0) ng/ml vs.(0.7±0.4) ng/ml, P=0.008;(3.0±2.0) ng/ml vs.(0.9±0.5) ng/ml, P=0.023]. Compared with NC group, subcutaneous resistin increased [(1.6±1.3) ng/ml vs.(3.5±1.4) ng/ml, P=0.041] while visceral leptin reduced[(15.1±11.5) ng/ml vs.(1.7±0.4) ng/ml, P=0.046] in OC group. In contrast to OC group, subcutaneous resistin decreased and visceral resistin elevated in RYGB group[(3.5±1.4)ng/ml vs(.1.7±0.7)ng/ml, P=0.012;(3.5±1.4) ng/ml vs.(1.8±1.1) ng/ml, P=0.051]; subcutaneous resistin did not decreased signicantly [(3.5±1.4) ng/ml vs.(1.8±1.1) ng/ml, P=0.051] while visceral resistin elevated [(1.7±0.4) ng/ml vs.(2.2±0.3) ng/ml, P=0.034]in SG group. Compared with NC group, subcutaneous adiponectin did not change significantly in OC group[(2.3±1.3) ng/ml vs.(2.1±1.9) ng/ml, P=0.833], while visceral adiponectin reduced[(3.3±1.3) ng/ml vs.(1.1±0.6) ng/ml, P=0.010]. In contrast to OC group, subcutaneous adiponectin did not change greatly in RYGB group[(2.1±1.9) ng/ml vs.(0.8±0.9) ng/ml, P=0.129]or SG group[(2.1±1.9) ng/ml vs.(2.3±1.69) ng/ml, P=0.856], while visceral adiponectin reduced[(1.1±0.6) ng/ml vs.(0.9±0.6) ng/ml, P=0.598;(1.1±0.6) ng/ml vs.(0.5±0.1) ng/ml, P=0.024]. Compared with NC group, leptin, resistin and adiponectin increased in circulation of OC group[(0.3±0.1) ng/ml vs.(1.2±0.3) ng/ml, P=0.000;(1.4±0.3) ng/ml vs.(14.4±5.3) ng/ml, P=0.000;(0.6±0.1) ng/ml vs.(17.2±1.2) ng/ml, P=0.000]. In contrast to OC group, serum leptin and adiponectin decreased in RYGB group[(1.2±0.3) ng/ml vs.(0.3±0.1) ng/ml, P=0.000;(17.2±1.2) ng/ml vs.(10.6±2.9) ng/ml,P=0.000] and SG group[(1.2±0.3)ng/ml vs.(0.4±0.3)ng/ml, P=0.002;(17.2±1.2) ng/ml vs.(11.3±2.9) ng/ml, P=0.000], while serum resistin did not reduced significantly in RYGB group[(14.4±5.3) ng/ml vs.(9.7±2.8) ng/ml, P=0.066] and SG group[(14.4±5.3) ng/ml vs.(11.4±6.5) ng/ml, P=0.454]. Compared with NC group, subcutaneous PPARy increased in OC group[(0.4±0.2) pg/ml vs.(1.6±0.4) pg/ml, P=0.000], while visceral PPARy decreased[(1.4±0.5)pg/ml vs.(0.6±0.3)pg/ml, P=0.016]. In contrast to OC group, subcutaneous PPARy decreased in RYGB group[(1.6±0.4) pg/ml vs.(0.3±0.1) pg/ml, P=0.000] and SG group[(1.6±0.4) pg/ml vs.(0.5±0.2) pg/ml, P=0.000], while visceral PPARy did not decreased significantly in RYGB group[(0.7±0.3) pg/ml vs.(0.6±0.3) pg/ml, P=0.598] or in SG group[(1.4±0.7) pg/ml vs.(0.6±0.3) pg/ml, P=0.061]. In obese rats, subcutaneous PPARy positively correlated with body weight (r=0.731, P=0.049), while subcutaneous PPARy and leptin positively related with serum leptin (r=0.936, P=0.002; r=0.772, P=0.042).
Conclusions Both obese rodent model and bariatric surgical models were established successfully one after another. PPARy, leptin or resistin elevated in circulation of obese rats, and so did HOMA-IR. The elevated PPARy and leptin decreased after weight loss surgeries, and HOMA-IR also reduced. So it's possible that weight loss surgery or metabolic surgery improve insulin resistance through decreased PPARy and leptin.
引文
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[7]中华医学会外科学分会内分泌外科学组,中华医学会外科学分会胃肠外科学组,中华医学会外科学分会手术学学组,中华医学会外科学分会腹腔镜与内镜外科学组.中国糖尿病外科治疗专家指导意见[J].中国实用外科杂志,2011,31(1)：54-58.
[8]中华医学会外科学分会内分泌外科学组,中华医学会外科学分会腹腔镜与内镜外科学组,中华医学会外科学分会胃肠外科学组,中华医学会外科学分会外科手术学学组.中国肥胖病外科治疗指南(2007)[J].中国实用外科杂志,2007,27(10)：759-762
[9]Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery:systematic review and meta-analysis[J]. Am J Med,2009,122(3):248-256.
[10]Cummings DE. Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery[J]. Int J Obes (Lond),2009,33 Suppl 1:S33-S40.
[11]Cox HM. Peptide YY:a neuroendocrine neighbor of note[J]. Peptides,2007,28(2):345-351.
[12]Maljaars PW, Keszthelyi D, Masclee AA. An ileal brake-through [J].? Am J Clin Nutr,2010, 92(3):467-468.
[13]Mingrone G, Castagneto-Gissey L. Mechanisms of early improvement/resolution of type 2 diabetes after bariatric surgery[J]. Diabetes Metab,2009,35(6 Pt 2):518-523.
[14]Thaler JP, Cummings DE. Minireview:Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery[J]. Endocrinology,2009,150(6):2518-2525.
[15]Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after Gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes[J]. Ann Surg,2006,244(5):741-749.
[16]张化冰,杜颖,肖新华.改善胰岛素抵抗一预防和治疗2型糖尿病的关键[J].中华内分泌代谢杂志,2011,27(1)：增录1b1-1b2
[17]Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease[J]. Diabetes,1988, 37(12):1595-1607.
[18]Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature,2006,444(7121):840-846.
[19]Tataranni PA. Pathophysiology of obesity-induced insulin resistance and type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci,2002,6(2-3):27-32.
[20]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue[J]. Nature,1994,372(6505):425-432.
[21]Whitson BA, Leslie DB, Kellogg TA, et al. Adipokine response in diabetics and nondiabetics following the Roux-en-Y gastric bypass:a preliminary study[J]. J Surg Res,2007,142(2):295-300.
[22]Steppan CM, Lazar MA. Resistin and obesity-associated insulin resistance[J].Trends Endocrinol Metab,2002,13(1):18-23.
[23]Steppan CM, Bailey ST, Bhat S, et al.The hormone resistin links obesity to diabetes[J].Nature, 2001,409(6818):307-312.
[24]Ziemke F, Mantzoros CS.Adiponectin in insulin resistance:lessons from translational research[J]. Am J Clin Nutr,2010,91(1):258S-261S.
[25]Wajchenberg BL, Giannella-Neto D, da Silva ME, et al. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome[J]. Horm Metab Res,2002,34(11-12):616-621.
[26]Montague CT, O'Rahilly S. The perils of portliness:causes and consequences of visceral adiposity[J]. Diabetes,2000,49(6):883-888.
[27]Wajchenberg BL.Subcutaneous and visceral adipose tissue:their relation to the metabolic syndrome[J]. Endocr Rev,2000,21(6):697-738.
[28]Goodpaster BH, Thaete FL, Simoneau JA, et al. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat[J]. Diabetes,1997, 46(10):1579-1585.
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[31]Vidal-Puig A, Jimenez-Linan M, Lowell BB, et al. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents[J]. J Clin Invest,1996,97(11):2553-2561.
[32]Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets[J]. Circulation,2007,115(4):518-533.
[33]Sugii S, Olson P, Sears DD, et al. PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization[J]. Proc Natl Acad Sci U S A,2009,106(52):22504-22509.
[34]Kahn BB, McGraw TE. Rosiglitazone, PPARy, and type 2 diabetes[J]. N Engl J Med,2010, 363(27):2667-2669.
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[37]Samaras K, Botelho NK, Chisholm DJ, et al. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes[J]. Obesity (Silver Spring),2010, 18(5):884-889.
[38]Onat A, Ugur M, Can G, et al. Visceral adipose tissue and body fat mass:predictive values for and role of gender in cardiometabolic risk among Turks[J]. Nutrition,2010,26(4):382-389.
[39]Jensen MD. Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model[J]. Obesity (Silver Spring),2006,14 Suppl 1:20S-24S.
[40]顾卫琼,洪洁张翼飞,等.肥胖人群中血清瘦素、游离脂肪酸和脂联素水平的相互关系[J].中华内分泌代谢杂志,2003,19(3)：169-172.
[41]Hivert MF, Sullivan LM, Fox CS, et al. Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. J Clin Endocrinol Metab,2008,93(8):3165-3172.
[42]Tian L, Shen H, Lu Q, et al. Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. J Clin Endocrinol Metab,2007,92(4):1430-1433.
[43]Fabbrini E, Tamboli RA, Magkos F, et al. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults[J]. Gastroenterology,2010, 139(2):448-455.
[44]Sharma AM, Staels B. Review:Peroxisome proliferator-activated receptor gamma and adipose tissue-understanding obesity-related changes in regulation of lipid and glucose metabolism[J]. J Clin Endocrinol Metab,2007,92(2):386-395.
[45]Heidemann C, Sun Q, van Dam RM, et al. Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women[J]. Ann Intern Med,2008, 149(5):307-316.
[46]Dardeno TA, Chou SH, Moon HS, et al. Leptin in human physiology and therapeutics[J]. Front Neuroendocrinol,2010,31(3):377-393.
[47]Rhie YJ, Choi BM, Eun SH, et al. Association of serum retinol binding protein 4 with adiposity and pubertal development in korean children and adolescents[J]. J Korean Med Sci,2011, 26(6):797-802.
[48]Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments:association with metabolic risk factors in the Framingham Heart Study [J]. Circulaton,2007,116:39-48.
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[1]Colquitt JL, Picot J, Loveman E, et al. Surgery for obesity[J]. Cochrane Database Syst Rev,2009, 15 (2):CD003641.
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[3]Rubino F, Kaplan LM, Schauer PR, et al. The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus[J]. Ann Surg,2010,251 (3):399-405.
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[21]Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance[J]. Gastroenterology,2007,132(6):2169-2180.
[22]Joao Cabrera E, Valezi AC, Delfino VD, et al. Reduction in plasma levels of inflammatory and oxidative stress indicators after Roux-en-Y gastric bypass[J]. Obes Surg,2010,20(1):42-49.
[2]Gu D, He J, Duan X, et al. Body weight and mortality among men and women in ChinafJ]. JAMA, 2006,295(7):776-783.
[3]Colquitt JL, Picot J, Loveman E, et al. Surgery for obesity[J]. Cochrane Database Syst Rev,2009, 15:CD003641.
[4]Rubino F. Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis[J]. Diabetes Care,2008,31:S290-S296.
[5]Rubino F, Kaplan LM, Schauer PR, et al. The Diabetes Surgery Summit consensus conference: recommendations for the evaluation and use of gastrointestinal surgery to treat type 2 diabetes mellitus[J].. Ann Surg,2010,251(3):399-405.
[6]American Diabetes Association. The American Diabetes Association (ADA) has been actively involved in the development and dissemination of diabetes care standards, guideline, and related documents for many years. Introduction[J]. Diabetes Care,2009,32 Suppl 1:S1-S2.
[7]中华医学会外科学分会内分泌外科学组,中华医学会外科学分会胃肠外科学组,中华医学会外科学分会手术学学组,中华医学会外科学分会腹腔镜与内镜外科学组.中国糖尿病外科治疗专家指导意见[J].中国实用外科杂志,2011,31(1)：54-58.
[8]中华医学会外科学分会内分泌外科学组,中华医学会外科学分会腹腔镜与内镜外科学组,中华医学会外科学分会胃肠外科学组,中华医学会外科学分会外科手术学学组.中国肥胖病外科治疗指南(2007)[J].中国实用外科杂志,2007,27(10)：759-762
[9]Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2 diabetes after bariatric surgery:systematic review and meta-analysis[J]. Am J Med,2009,122(3):248-256.
[10]Cummings DE. Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery[J]. Int J Obes (Lond),2009,33 Suppl 1:S33-S40.
[11]Cox HM. Peptide YY:a neuroendocrine neighbor of note[J]. Peptides,2007,28(2):345-351.
[12]Maljaars PW, Keszthelyi D, Masclee AA. An ileal brake-through [J].? Am J Clin Nutr,2010, 92(3):467-468.
[13]Mingrone G, Castagneto-Gissey L. Mechanisms of early improvement/resolution of type 2 diabetes after bariatric surgery[J]. Diabetes Metab,2009,35(6 Pt 2):518-523.
[14]Thaler JP, Cummings DE. Minireview:Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery[J]. Endocrinology,2009,150(6):2518-2525.
[15]Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after Gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes[J]. Ann Surg,2006,244(5):741-749.
[16]张化冰,杜颖,肖新华.改善胰岛素抵抗一预防和治疗2型糖尿病的关键[J].中华内分泌代谢杂志,2011,27(1)：增录1b1-1b2
[17]Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease[J]. Diabetes,1988, 37(12):1595-1607.
[18]Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature,2006,444(7121):840-846.
[19]Tataranni PA. Pathophysiology of obesity-induced insulin resistance and type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci,2002,6(2-3):27-32.
[20]Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue[J]. Nature,1994,372(6505):425-432.
[21]Whitson BA, Leslie DB, Kellogg TA, et al. Adipokine response in diabetics and nondiabetics following the Roux-en-Y gastric bypass:a preliminary study[J]. J Surg Res,2007,142(2):295-300.
[22]Steppan CM, Lazar MA. Resistin and obesity-associated insulin resistance[J].Trends Endocrinol Metab,2002,13(1):18-23.
[23]Steppan CM, Bailey ST, Bhat S, et al.The hormone resistin links obesity to diabetes[J].Nature, 2001,409(6818):307-312.
[24]Ziemke F, Mantzoros CS.Adiponectin in insulin resistance:lessons from translational research[J]. Am J Clin Nutr,2010,91(1):258S-261S.
[25]Wajchenberg BL, Giannella-Neto D, da Silva ME, et al. Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome[J]. Horm Metab Res,2002,34(11-12):616-621.
[26]Montague CT, O'Rahilly S. The perils of portliness:causes and consequences of visceral adiposity[J]. Diabetes,2000,49(6):883-888.
[27]Wajchenberg BL.Subcutaneous and visceral adipose tissue:their relation to the metabolic syndrome[J]. Endocr Rev,2000,21(6):697-738.
[28]Goodpaster BH, Thaete FL, Simoneau JA, et al. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat[J]. Diabetes,1997, 46(10):1579-1585.
[29]Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5[J]. Nature,2010,466(7305):451-456.
[30]Samarasinghe SP, Sutanto MM, Danos AM, et al. Altering PPARgamma ligand selectivity impairs adipogenesis by thiazolidinediones but not hormonal inducers[J]. Obesity (Silver Spring),2009, 17(5):965-972.
[31]Vidal-Puig A, Jimenez-Linan M, Lowell BB, et al. Regulation of PPAR gamma gene expression by nutrition and obesity in rodents[J]. J Clin Invest,1996,97(11):2553-2561.
[32]Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets[J]. Circulation,2007,115(4):518-533.
[33]Sugii S, Olson P, Sears DD, et al. PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization[J]. Proc Natl Acad Sci U S A,2009,106(52):22504-22509.
[34]Kahn BB, McGraw TE. Rosiglitazone, PPARy, and type 2 diabetes[J]. N Engl J Med,2010, 363(27):2667-2669.
[35]Hansen D, Dendale P, Beelen M, et al. Plasma adipokine and inflammatory marker concentrations are altered in obese, as opposed to non-obese, type 2 diabetes patients[J]. Eur J Appl Physiol, 2010,109(3):397-404.
[36]Baranova A, Gowder SJ, Schlauch K, et al. Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance[J]. Obes Surg,2006,16(9):1118-1125.
[37]Samaras K, Botelho NK, Chisholm DJ, et al. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes[J]. Obesity (Silver Spring),2010, 18(5):884-889.
[38]Onat A, Ugur M, Can G, et al. Visceral adipose tissue and body fat mass:predictive values for and role of gender in cardiometabolic risk among Turks[J]. Nutrition,2010,26(4):382-389.
[39]Jensen MD. Is visceral fat involved in the pathogenesis of the metabolic syndrome? Human model[J]. Obesity (Silver Spring),2006,14 Suppl 1:20S-24S.
[40]顾卫琼,洪洁张翼飞,等.肥胖人群中血清瘦素、游离脂肪酸和脂联素水平的相互关系[J].中华内分泌代谢杂志,2003,19(3)：169-172.
[41]Hivert MF, Sullivan LM, Fox CS, et al. Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance. J Clin Endocrinol Metab,2008,93(8):3165-3172.
[42]Tian L, Shen H, Lu Q, et al. Insulin resistance increases the risk of spontaneous abortion after assisted reproduction technology treatment. J Clin Endocrinol Metab,2007,92(4):1430-1433.
[43]Fabbrini E, Tamboli RA, Magkos F, et al. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults[J]. Gastroenterology,2010, 139(2):448-455.
[44]Sharma AM, Staels B. Review:Peroxisome proliferator-activated receptor gamma and adipose tissue-understanding obesity-related changes in regulation of lipid and glucose metabolism[J]. J Clin Endocrinol Metab,2007,92(2):386-395.
[45]Heidemann C, Sun Q, van Dam RM, et al. Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women[J]. Ann Intern Med,2008, 149(5):307-316.
[46]Dardeno TA, Chou SH, Moon HS, et al. Leptin in human physiology and therapeutics[J]. Front Neuroendocrinol,2010,31(3):377-393.
[47]Rhie YJ, Choi BM, Eun SH, et al. Association of serum retinol binding protein 4 with adiposity and pubertal development in korean children and adolescents[J]. J Korean Med Sci,2011, 26(6):797-802.
[48]Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments:association with metabolic risk factors in the Framingham Heart Study [J]. Circulaton,2007,116:39-48.
[49]Kissebah AH, Krakower GR. Regional adiposity and morbidity[J]. Physiol Rev,1994,74:761-811.
[50]Stefater MA, Perez-Tilve D, Chambers AP, et al. Sleeve gastrectomy induces loss of weight and fat mass in obese rats, but does not affect leptin sensitivity[J]. Gastroenterology,2010, 138(7):2426-2436,2436.e1-e3.
[51]Xu Y, Ohinata K, Meguid MM, et al. Gastric bypass model in the obese rat to study metabolic mechanisms of weight loss[J]. J Surg Res,2002,107(1):56-63.
[52]Meguid MM, Ramos EJ, Suzuki S, et al. A surgical rat model of human Roux-en-Y gastric bypass[J]. J Gastrointest Surg,2004,8(5):621-630.
[53]汤锦华,严海东.营养性肥胖大鼠模型的建立及评价[J].同济大学学报(医学版),2010,31(1)：32-34.
[54]Scarpace PJ, Zhang Y. Leptin resistance:a prediposing factor for diet-induced obesity[J]. Am J Physiol Regul Integr Comp Physiol,2009,296(3):R493-R500.
[55]Novak CM, Kotz CM, Levine JA. Central orexin sensitivity, physical activity, and obesity in diet-induced obese and diet-resistant rats[J]. Am J Physiol Endocrinol Metab,2006, 290(2):E396-E403.
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