Hagman Derek K, Larson Ilona, Kuzma Jessica N, Cromer Gail, Makar Karen, Rubinow Katya B, Foster-Schubert Karen E, van Yserloo Brian, Billing Peter S, Landerholm Robert W, Crouthamel Matthew, Flum David R, Cummings David E, Kratz Mario
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Diabetes Research Center, University of Washington, Seattle, WA 98195, USA.
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Metabolism. 2017 May;70:12-22. doi: 10.1016/j.metabol.2017.01.030. Epub 2017 Feb 2.
The mechanisms mediating the short- and long-term improvements in glucose homeostasis following bariatric/metabolic surgery remain incompletely understood.
To investigate whether a reduction in adipose tissue inflammation plays a role in the metabolic improvements seen after bariatric/metabolic surgery, both in the short-term and longer-term.
Fasting blood and subcutaneous abdominal adipose tissue were obtained before (n=14), at one month (n=9), and 6-12months (n=14) after bariatric/metabolic surgery from individuals with obesity who were not on insulin or anti-diabetes medication. Adipose tissue inflammation was assessed by a combination of whole-tissue gene expression and flow cytometry-based quantification of tissue leukocytes.
One month after surgery, body weight was reduced by 13.5±4.4kg (p<0.001), with improvements in glucose tolerance reflected by a decrease in area-under-the-curve (AUC) glucose in 3-h oral glucose tolerance tests (-105±98mmol/L * min; p=0.009) and enhanced pancreatic β-cell function (insulinogenic index: +0.8±0.9pmol/mmol; p=0.032), but no change in estimated insulin sensitivity (Matsuda insulin sensitivity index [ISI]; p=0.720). Furthermore, although biomarkers of systemic inflammation and pro-inflammatory gene expression in adipose tissue remained unchanged, the number of neutrophils increased in adipose tissue 15-20 fold (p<0.001), with less substantial increases in other leukocyte populations. By the 6-12month follow-up visit, body weight was reduced by 34.8±10.8kg (p<0.001) relative to baseline, and glucose tolerance was further improved (AUC glucose -276±229; p<0.001) along with estimated insulin sensitivity (Matsuda ISI: +4.6±3.2; p<0.001). In addition, improvements in systemic inflammation were reflected by reductions in circulating C-reactive protein (CRP; -2.0±5.3mg/dL; p=0.002), and increased serum adiponectin (+1358±1406pg/mL; p=0.003). However, leukocyte infiltration of adipose tissue remained elevated relative to baseline, with pro-inflammatory cytokine mRNA expression unchanged, while adiponectin mRNA expression trended downward (p=0.069).
Both the short- and longer-term metabolic improvements following bariatric/metabolic surgery occur without significant reductions in measures of adipose tissue inflammation, as assessed by measuring the expression of genes encoding key mediators of inflammation and by flow cytometric immunophenotyping and quantification of adipose tissue leukocytes.
减肥/代谢手术后血糖稳态短期和长期改善的介导机制仍未完全明确。
研究脂肪组织炎症减轻在减肥/代谢手术后短期和长期代谢改善中是否起作用。
从未使用胰岛素或抗糖尿病药物的肥胖个体中，在减肥/代谢手术前（n = 14）、术后1个月（n = 9）和6 - 12个月（n = 14）获取空腹血液和腹部皮下脂肪组织。通过全组织基因表达和基于流式细胞术的组织白细胞定量相结合的方法评估脂肪组织炎症。
术后1个月，体重减轻了13.5±4.4kg（p<0.001），葡萄糖耐量得到改善，表现为3小时口服葡萄糖耐量试验中曲线下面积（AUC）葡萄糖降低（-105±98mmol/L * min；p = 0.009），胰腺β细胞功能增强（胰岛素生成指数：+0.8±0.9pmol/mmol；p = 0.032），但估计的胰岛素敏感性无变化（松田胰岛素敏感性指数[ISI]；p = 0.720）。此外，尽管全身炎症生物标志物和脂肪组织中促炎基因表达未改变，但脂肪组织中中性粒细胞数量增加了15 - 20倍（p<0.001），其他白细胞群体增加幅度较小。到6 - 12个月随访时，体重相对于基线减轻了34.8±10.8kg（p<0.001），葡萄糖耐量进一步改善（AUC葡萄糖 -276±229；p<0.001），同时估计的胰岛素敏感性也得到改善（松田ISI：+4.6±3.2；p<0.001）。此外，全身炎症的改善表现为循环C反应蛋白（CRP）降低（-2.0±5.3mg/dL；p = 0.002），血清脂联素增加（+1358±1406pg/mL；p = 0.003）。然而，相对于基线，脂肪组织中的白细胞浸润仍然升高，促炎细胞因子mRNA表达未改变，而脂联素mRNA表达呈下降趋势（p = 0.069）。
通过测量编码炎症关键介质的基因表达以及通过流式细胞术免疫表型分析和定量脂肪组织白细胞评估，减肥/代谢手术后短期和长期的代谢改善均未伴随着脂肪组织炎症指标的显著降低而发生。
