Ye Risheng, Wang Miao, Wang Qiong A, Scherer Philipp E
Touchstone Diabetes Center (R.Y., Q.A.W., P.E.S.), Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Hamon Center for Therapeutic Oncology Research (M.W.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Department of Cell Biology (P.E.S.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
Endocrinology. 2015 Jun;156(6):2019-28. doi: 10.1210/en.2015-1066. Epub 2015 Mar 27.
Pathways that stimulate β-cell regeneration remain of great clinical interest, yet effective therapeutic avenues that promote survival or reconstitution of β-cell mass remain elusive. Using a mouse model with inducible β-cell apoptosis followed by adiponectin-mediated regeneration, we aimed to identify key molecules boosting β-cell viability. In the regenerating pancreatic islets, we examined changes within the transcriptome and observed an extensive up-regulation of genes encoding proteins involved in lipid transport and metabolism. The most prominent targets were further confirmed by quantitative PCR and immunofluorescence. Among the upstream regulators predicted by pathway analysis of the transcriptome, we detected enhanced levels of 2 key transcription factors, Hepatocyte Nuclear Factor 4α and Peroxisome Proliferator-Activated Receptorα. Our data suggest that improving pancreatic islet lipid metabolism as an important antilipotoxic phenomenon to boost β-cell regeneration. This is primarily mediated by the adipokine adiponectin that exerts its action on both the beta-cell directly as well as on the adipocyte. Adiponectin induces lipid metabolism gene expression in regenerating islets through Hepatocyte Nuclear Factor 4α and Peroxisome Proliferator-Activated Receptorα. Adiponectin also modulates leptin levels via preserving adipose tissue mass in the insulinopenic state.
刺激β细胞再生的途径仍具有重大临床意义，但促进β细胞团存活或重建的有效治疗途径仍不明确。我们使用一种可诱导β细胞凋亡并随后进行脂联素介导的再生的小鼠模型，旨在确定增强β细胞活力的关键分子。在再生的胰岛中，我们检查了转录组内的变化，并观察到编码参与脂质转运和代谢的蛋白质的基因广泛上调。通过定量PCR和免疫荧光进一步证实了最突出的靶点。在通过转录组通路分析预测的上游调节因子中，我们检测到2种关键转录因子——肝细胞核因子4α和过氧化物酶体增殖物激活受体α的水平升高。我们的数据表明，改善胰岛脂质代谢是促进β细胞再生的一种重要的抗脂毒性现象。这主要由脂肪因子脂联素介导，脂联素对β细胞和脂肪细胞都发挥作用。脂联素通过肝细胞核因子4α和过氧化物酶体增殖物激活受体α诱导再生胰岛中的脂质代谢基因表达。脂联素还通过在胰岛素缺乏状态下维持脂肪组织质量来调节瘦素水平。
