Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Mol Cell. 2020 Jul 2;79(1):43-53.e4. doi: 10.1016/j.molcel.2020.04.033. Epub 2020 May 27.
The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.
免疫细胞在调节餐后葡萄糖代谢中的生理作用尚未完全阐明。我们发现，脂肪组织巨噬细胞在进食后会产生白细胞介素-10（IL-10），它与胰岛素协同抑制肝葡萄糖生成。进食后，升高的胰岛素和肠道微生物群衍生的脂多糖通过 Akt/雷帕霉素靶蛋白（mTOR）途径促进 IL-10 的产生。事实上，髓样细胞特异性敲除胰岛素受体或骨髓移植突变 TLR4 骨髓细胞会导致糖异生基因表达增加和葡萄糖耐量受损。此外，髓样细胞特异性 Akt1 和 Akt2 敲除会导致类似的表型，而 mTOR 抑制剂 TSC2 的额外敲除可以挽救这些表型。在肥胖中，由于巨噬细胞中的胰岛素抵抗，IL-10 的产生受损，而腺病毒介导的 IL-10 表达可改善餐后高血糖。因此，内源性激素和肠道环境对进食的协调反应是调节餐后血糖的关键因素。
