SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice

Haruhisa Iguchi, Yukio Ikeda, Masashi Okamura, Toshiya Tanaka, Yasuyo Urashima, Hiroto Ohguchi, Shinobu Takayasu, Noriaki Kojima, Satoshi Iwasaki, Riuko Ohashi, Shuying Jiang, Go Hasegawa, Ryoichi X. Ioka, Kenta Magoori, Koichi Sumi, Takashi Maejima, Aoi Uchida, Makoto Naito, Timothy F. Osborne, Masashi YanagisawaTokuo T. Yamamoto, Tatsuhiko Kodama, Juro Sakai

Research output: Contribution to journalArticle

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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 β-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca2+ 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 β-cells may contribute to the β-cell adaptation in obesity-related insulin resistance.

Original languageEnglish (US)
Pages (from-to)37669-37680
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number45
DOIs
StatePublished - Nov 11 2005

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Obese Mice
Insulin
Glucose
Insulin Resistance
Histones
Chromatin
Obesity
Proinsulin
Co-Repressor Proteins
Insulinoma
Acetylation
Islets of Langerhans
Adenosine Diphosphate
Small Interfering RNA
Proteins
Transcription Factors
Adenosine Triphosphate
Fats
Nutrition
Diet

ASJC Scopus subject areas

  • Biochemistry

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SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. / Iguchi, Haruhisa; Ikeda, Yukio; Okamura, Masashi; Tanaka, Toshiya; Urashima, Yasuyo; Ohguchi, Hiroto; Takayasu, Shinobu; Kojima, Noriaki; Iwasaki, Satoshi; Ohashi, Riuko; Jiang, Shuying; Hasegawa, Go; Ioka, Ryoichi X.; Magoori, Kenta; Sumi, Koichi; Maejima, Takashi; Uchida, Aoi; Naito, Makoto; Osborne, Timothy F.; Yanagisawa, Masashi; Yamamoto, Tokuo T.; Kodama, Tatsuhiko; Sakai, Juro.

In: Journal of Biological Chemistry, Vol. 280, No. 45, 11.11.2005, p. 37669-37680.

Research output: Contribution to journalArticle

Iguchi, H, Ikeda, Y, Okamura, M, Tanaka, T, Urashima, Y, Ohguchi, H, Takayasu, S, Kojima, N, Iwasaki, S, Ohashi, R, Jiang, S, Hasegawa, G, Ioka, RX, Magoori, K, Sumi, K, Maejima, T, Uchida, A, Naito, M, Osborne, TF, Yanagisawa, M, Yamamoto, TT, Kodama, T & Sakai, J 2005, 'SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice', Journal of Biological Chemistry, vol. 280, no. 45, pp. 37669-37680. https://doi.org/10.1074/jbc.M505392200
Iguchi, Haruhisa ; Ikeda, Yukio ; Okamura, Masashi ; Tanaka, Toshiya ; Urashima, Yasuyo ; Ohguchi, Hiroto ; Takayasu, Shinobu ; Kojima, Noriaki ; Iwasaki, Satoshi ; Ohashi, Riuko ; Jiang, Shuying ; Hasegawa, Go ; Ioka, Ryoichi X. ; Magoori, Kenta ; Sumi, Koichi ; Maejima, Takashi ; Uchida, Aoi ; Naito, Makoto ; Osborne, Timothy F. ; Yanagisawa, Masashi ; Yamamoto, Tokuo T. ; Kodama, Tatsuhiko ; Sakai, Juro. / SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 45. pp. 37669-37680.
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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 β-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca2+ 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 β-cells may contribute to the β-cell adaptation in obesity-related insulin resistance.",
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T1 - SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice

AU - Iguchi, Haruhisa

AU - Ikeda, Yukio

AU - Okamura, Masashi

AU - Tanaka, Toshiya

AU - Urashima, Yasuyo

AU - Ohguchi, Hiroto

AU - Takayasu, Shinobu

AU - Kojima, Noriaki

AU - Iwasaki, Satoshi

AU - Ohashi, Riuko

AU - Jiang, Shuying

AU - Hasegawa, Go

AU - Ioka, Ryoichi X.

AU - Magoori, Kenta

AU - Sumi, Koichi

AU - Maejima, Takashi

AU - Uchida, Aoi

AU - Naito, Makoto

AU - Osborne, Timothy F.

AU - Yanagisawa, Masashi

AU - Yamamoto, Tokuo T.

AU - Kodama, Tatsuhiko

AU - Sakai, Juro

PY - 2005/11/11

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N2 - 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 β-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca2+ 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 β-cells may contribute to the β-cell adaptation in obesity-related insulin resistance.

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