Deletion of Hypoxia-Inducible Factor-1α in Adipocytes Enhances Glucagon-Like Peptide-1 Secretion and Reduces Adipose Tissue Inflammation

It is known that obese adipose tissues are hypoxic and express hypoxia-inducible factor (HIF)-1α. Although some studies have shown that the expression of HIF-1α in adipocytes induces glucose intolerance, the mechanisms are still not clear. In this study, we examined its effects on the development of type 2 diabetes by using adipocyte-specific HIF-1α knockout (ahKO) mice. ahKO mice showed improved glucose tolerance compared with wild type (WT) mice. Macrophage infiltration and mRNA levels of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor α (TNFα) were decreased in the epididymal adipose tissues of high fat diet induced obese ahKO mice. The results indicated that the obesity-induced adipose tissue inflammation was suppressed in ahKO mice. In addition, in the ahKO mice, serum insulin levels were increased under the free-feeding but not the fasting condition, indicating that postprandial insulin secretion was enhanced. Serum glucagon-like peptide-1 (GLP-1) levels were also increased in the ahKO mice. Interestingly, adiponectin, whose serum levels were increased in the obese ahKO mice compared with the obese WT mice, stimulated GLP-1 secretion from cultured intestinal L cells. Therefore, insulin secretion may have been enhanced through the adiponectin-GLP-1 pathway in the ahKO mice. Our results suggest that the deletion of HIF-1α in adipocytes improves glucose tolerance by enhancing insulin secretion through the GLP-1 pathway and by reducing macrophage infiltration and inflammation in adipose tissue.

已知肥胖脂肪组织处于缺氧状态，并表达缺氧诱导因子-1α（hypoxia-inducible factor-1α，HIF-1α）。尽管已有研究证实，脂肪细胞内HIF-1α的表达可诱发糖耐量异常，但其具体调控机制尚未阐明。本研究通过构建脂肪细胞特异性缺氧诱导因子-1α敲除小鼠（adipocyte-specific HIF-1α knockout，ahKO），探讨了该因子在2型糖尿病发病进程中的作用。结果显示，与野生型（WT）小鼠相比，ahKO小鼠的糖耐量得到显著改善。高脂饮食诱导的肥胖ahKO小鼠的附睾脂肪组织中，巨噬细胞浸润程度以及单核细胞趋化蛋白-1（monocyte chemotactic protein-1，MCP-1）、肿瘤坏死因子α（tumor necrosis factor α，TNFα）的mRNA表达水平均显著降低，表明脂肪细胞HIF-1α缺失可抑制肥胖诱导的脂肪组织炎症反应。此外，在自由进食状态下，ahKO小鼠的血清胰岛素水平升高，而禁食状态下无此变化，提示餐后胰岛素分泌功能得到增强。同时，ahKO小鼠的血清胰高血糖素样肽-1（glucagon-like peptide-1，GLP-1）水平亦有所升高。值得注意的是，与肥胖WT小鼠相比，肥胖ahKO小鼠血清中的脂联素水平升高，而脂联素可刺激体外培养的肠道L细胞分泌GLP-1。据此推测，ahKO小鼠可能通过脂联素-GLP-1通路增强了胰岛素分泌。综上，本研究结果表明，脂肪细胞中HIF-1α的缺失可通过两条途径改善糖耐量：一是通过GLP-1通路增强胰岛素分泌，二是减少脂肪组织的巨噬细胞浸润与炎症反应。