Coordinate regulation of Wnt signaling and transcriptional factors in endocrine pancreatic islets in obese related insulin

Wnt辅助受体低密度脂蛋白受体相关蛋白5在骨生成和眼发育中起重要作用。在肥胖相关的胰岛素抵抗中，胰岛通过增加其分泌能力或增加胰岛细胞质量来补偿胰岛素抵抗。我们研究了胰岛中Wnt/β-catenin信号。在这里，我们报告的鉴定SOX 6，转录因子的HMG盒超家族的成员，作为胰腺十二指肠同源框因子-1（PDX 1）的共阻遏物。在正常小鼠和正常饮食的肥胖ob/ob小鼠中，长期高脂喂养可显著降低SOX 6 mRNA水平，SOX 6过表达可降低葡萄糖刺激的胰岛素分泌（GSIS），并伴有ATP/ADP比值、Ca^2+动员、胰岛素原含量和胰岛素基因表达的降低。在一个互补的方式，小干扰RNA的SOX 6消耗增强GSIS在胰岛素瘤小鼠MIN 6和大鼠INS-1 E细胞。这些作用可以通过我们的机制研究来解释，该研究表明SOX 6通过直接的蛋白质：蛋白质相互作用来抑制胰岛素II启动子的PDX 1刺激。此外，SOX 6逆转录病毒表达降低了来自胰岛素II基因启动子的染色质中组蛋白H3和H4的乙酰化，表明SOX 6可能通过改变特定启动子处的染色质结构来降低PDX 1刺激。我们还发现，SOX 6过表达导致参与线粒体氧化磷酸化的基因表达显著减少，其中大多数被PDX 1过表达上调，这表明SOX 6也可能作为其他PDX 1依赖基因的一般共阻遏物。此外，我们还证明了SOX 6通过与β-catenin物理相互作用，募集组蛋白脱乙酰酶1，抑制Wnt/β-catenin信号通路，并降低INS-1和NIH 3 T3细胞增殖。

A Wnt coreceptor low density lipoprotein receptor related protein 5 plays an essential role in bone accrual and eye development. In obesity-related insulin resistance, the pancreatic islets compensate for insulin resistance by increasing their secretory capacity or increasing islet cell mass. We investigated Wnt/β-catenin signal in pancreatic islet. Here, we report the identification of SOX6, a member of the HMG box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in the genetically obese ob/ob mice on a normal chow diet.Overexpression of SOX6 decreased glucose stimulated insulin secretion (GSIS) which was accompanied by decreased ATP/ADP ratio, Ca^<2+> mobilization, proinsulin content and insulin genes expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented GSIS in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein : protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of the histones H3 and H4 in chromatin from the promoter for the insulin II gene suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. We also show that SOX6 overexpression results in a marked reduction in the expression of genes involved in mitochondrial oxidative phosphorylation, most of which were reciprocally up-regulated by PDX1 overexpression, suggesting that SOX6 may also act as a general co-repressor of other PDX1 dependent genes. Furthermore, we also demonstrated that SOX6 inhibits Wnt/β-catenin signaling pathway by physically interacting with β-catenin, recruiting histone deacetylase 1 and reduces INS-1 and NIH3T3 cell proliferation.