Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland
Children's Research Center, University Children's Hospital, Zurich, Switzerland.
Diabetes. 2018 Jan;67(1):36-45. doi: 10.2337/db17-0637. Epub 2017 Oct 24.
We recently showed that interleukin (IL)-6-type cytokine signaling in adipocytes induces free fatty acid release from visceral adipocytes, thereby promoting obesity-induced hepatic insulin resistance and steatosis. In addition, IL-6-type cytokines may increase the release of leptin from adipocytes and by those means induce glucagon-like peptide 1 (GLP-1) secretion. We thus hypothesized that IL-6-type cytokine signaling in adipocytes may regulate insulin secretion. To this end, mice with adipocyte-specific knockout of gp130, the signal transducer protein of IL-6, were fed a high-fat diet for 12 weeks. Compared with control littermates, knockout mice showed impaired glucose tolerance and circulating leptin, GLP-1, and insulin levels were reduced. In line, leptin release from isolated adipocytes was reduced, and intestinal proprotein convertase subtilisin/kexin type 1 () expression, the gene encoding PC1/3, which controls GLP-1 production, was decreased in knockout mice. Importantly, treatment with the GLP-1 receptor antagonist exendin 9-39 abolished the observed difference in glucose tolerance between control and knockout mice. Ex vivo, supernatant collected from isolated adipocytes of gp130 knockout mice blunted expression and GLP-1 release from GLUTag cells. In contrast, glucose- and GLP-1-stimulated insulin secretion was not affected in islets of knockout mice. In conclusion, adipocyte-specific IL-6 signaling induces intestinal GLP-1 release to enhance insulin secretion, thereby counteracting insulin resistance in obesity.
我们最近表明，脂肪细胞中的白细胞介素 (IL)-6 型细胞因子信号会导致内脏脂肪细胞释放游离脂肪酸，从而促进肥胖引起的肝胰岛素抵抗和脂肪变性。此外，IL-6 型细胞因子可能会增加脂肪细胞中瘦素的释放，并通过这些方式诱导胰高血糖素样肽 1 (GLP-1) 的分泌。因此，我们假设脂肪细胞中的 IL-6 型细胞因子信号可能会调节胰岛素分泌。为此，我们用脂肪细胞特异性敲除 gp130（IL-6 的信号转导蛋白）的小鼠喂食高脂肪饮食 12 周。与对照组相比，敲除小鼠表现出葡萄糖耐量受损，循环瘦素、GLP-1 和胰岛素水平降低。与此一致的是，从分离的脂肪细胞中释放的瘦素减少，并且编码控制 GLP-1 产生的 PC1/3 的基因 proprotein convertase subtilisin/kexin type 1 () 的表达减少。重要的是，用 GLP-1 受体拮抗剂 exendin 9-39 治疗可消除对照组和敲除组小鼠之间葡萄糖耐量差异。在体外，从 gp130 敲除小鼠的分离脂肪细胞收集的上清液减弱了 GLUTag 细胞中表达和 GLP-1 的释放。相比之下，敲除小鼠胰岛中不受葡萄糖和 GLP-1 刺激的胰岛素分泌不受影响。总之，脂肪细胞特异性的 IL-6 信号诱导肠道 GLP-1 释放以增强胰岛素分泌，从而抵抗肥胖引起的胰岛素抵抗。
