| BackgroundWeight 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 ratsObjective 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.
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