SOX6 Attenuates Glucose-stimulated Insulin Secretion by Repressing PDX1 Transcriptional Actvity and Is Down-regulated in Hyperinsulinemic Obese Mice

Abstract

In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group 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 genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing ␤-cells and that overexpression of SOX6 decreased glucosestimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca 2؉ mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion 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 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. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in ␤-cells may contribute to the ␤-cell adaptation in obesity-related insulin resistance.

Nesfatin-1 Exerts a Direct, Glucose-Dependent Insulinotropic Action on Mouse Islet Beta and MIN6 Cells

“…NUCB2 mRNA increased twofold in the pancreas, and nesfatin-1-ir increased 37% above mice fed standard chow. This is in agreement with the fivefold increase in NUCB2 mRNA expression in the pancreatic islets of DIO mice, previously discovered in a microarray study (supplemental data in Iguchi et al 2005). We found significant increases in the density, size, and distribution of pancreatic islets in DIO mice, similar to previous reports of increases in islet mass in DIO mice (Reimer et al 2002, Bock et al 2003.…”

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

“…This result may be secondary to the recruitment of the histone methyltransferase Set7/9 by Pdx1 [147]. Similarly, the glucose-stimulated increase in histone H4 acetylation (another marker of active, open chromatin) at the insulin gene in both cell lines and islets by Pdx1 is consistent with its recruitment of the histone acetyltransferase p300 [145,153,154]. These results suggest that an important component of gene activation by the Pdx1 protein complex may be its direct alteration of chromatin to a more open state, thereby permitting enhanced accessibility to other transcription factors and the basal transcriptional machinery.…”

Sox6 is required for normal fiber type differentiation of fetal skeletal muscle in mice

“…6). To date, the genes reported to be repressed by Sox6 in a wide variety of tissues include the insulin II (Iguchi et al, 2005), cyclin D1 (Iguchi et al, 2007), fgf-3 (Murakami et al, 2001), epsilon globin (Yi et al, 2006), and myelin genes (Stolt et al, 2006). Our current report adds MyHC-␤ to this list as a muscle specific gene repressed by Sox6.…”

“…Sox6 has been shown to suppress transcription of the insulin II gene in pancreatic cells (Iguchi et al, 2005). The authors suggest that the Sox6 protein functions as a repressor by blocking an activator on the promoter to initiate transcription.…”