Malpique Rita, Figueiredo Hugo, Esteban Yaiza, Rebuffat Sandra A, Hanzu Felicia A, Vinaixa Maria, Yanes Oscar, Correig Xavier, Barceló-Batllori Sílvia, Gasa Rosa, Kalko Susana G, Gomis Ramon
Diabetes and Obesity Laboratory, Institut d'Investigations Biomediques August Pi I Sunyer (IDIBAPS), Carrer Rosselló 153, 08036, Barcelona, Spain.
Diabetologia. 2014 Jun;57(6):1219-31. doi: 10.1007/s00125-014-3205-0. Epub 2014 Mar 15.
AIMS/HYPOTHESIS: Comprehensive characterisation of the interrelation between the peripancreatic adipose tissue and the pancreatic islets promises novel insights into the mechanisms that regulate beta cell adaptation to obesity. Here, we sought to determine the main pathways and key molecules mediating the crosstalk between these two tissues during adaptation to obesity by the way of an integrated inter-tissue, multi-platform analysis.
Wistar rats were fed a standard or cafeteria diet for 30 days. Transcriptomic variations by diet in islets and peripancreatic adipose tissue were examined through microarray analysis. The secretome from peripancreatic adipose tissue was subjected to a non-targeted metabolomic and proteomic analysis. Gene expression variations in islets were integrated with changes in peripancreatic adipose tissue gene expression and protein and metabolite secretion using an integrated inter-tissue pathway and network analysis.
The highest level of data integration, linking genes differentially expressed in both tissues with secretome variations, allowed the identification of significantly enriched canonical pathways, such as the activation of liver/retinoid X receptors, triacylglycerol degradation, and regulation of inflammatory and immune responses, and underscored interaction network hubs, such as cholesterol and the fatty acid binding protein 4, which were unpredicted through single-tissue analysis and have not been previously implicated in the peripancreatic adipose tissue crosstalk with beta cells.
CONCLUSIONS/INTERPRETATION: The integrated analysis reported here allowed the identification of novel mechanisms and key molecules involved in peripancreatic adipose tissue interrelation with beta cells during the development of obesity; this might help the development of novel strategies to prevent type 2 diabetes.
目的/假设：全面表征胰腺周围脂肪组织与胰岛之间的相互关系，有望为调节β细胞对肥胖适应的机制提供新见解。在此，我们试图通过综合组织间多平台分析，确定肥胖适应过程中这两种组织间相互作用的主要途径和关键分子。
将Wistar大鼠喂食标准饮食或自助餐饮食30天。通过微阵列分析检查胰岛和胰腺周围脂肪组织中饮食引起的转录组变化。对胰腺周围脂肪组织的分泌蛋白组进行非靶向代谢组学和蛋白质组学分析。使用综合组织间途径和网络分析，将胰岛中的基因表达变化与胰腺周围脂肪组织的基因表达、蛋白质和代谢物分泌变化整合在一起。
通过将两种组织中差异表达的基因与分泌蛋白组变化相联系，实现了最高水平的数据整合，从而确定了显著富集的经典途径，如肝/视黄醇X受体的激活、三酰甘油降解以及炎症和免疫反应的调节，并突出了相互作用网络枢纽，如胆固醇和脂肪酸结合蛋白4，这些在单组织分析中未被预测，且此前未涉及胰腺周围脂肪组织与β细胞的相互作用。
结论/解读：本文报道的综合分析确定了肥胖发生过程中胰腺周围脂肪组织与β细胞相互关系的新机制和关键分子；这可能有助于开发预防2型糖尿病的新策略。
