SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice.
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 beta-cells and that overexpression of SOX6 decreased glucose-stimulated 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 beta-cells may contribute to the beta-cell adaptation in obesity-related insulin resistance.
Iguchi
Haruhisa
H
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Japan.
Ikeda
Yukio
Y
Okamura
Masashi
M
Tanaka
Toshiya
T
Urashima
Yasuyo
Y
Ohguchi
Hiroto
H
Takayasu
Shinobu
S
Kojima
Noriaki
N
Iwasaki
Satoshi
S
Ohashi
Riuko
R
Jiang
Shuying
S
Hasegawa
Go
G
Ioka
Ryoichi X
RX
Magoori
Kenta
K
Sumi
Koichi
K
Maejima
Takashi
T
Uchida
Aoi
A
Naito
Makoto
M
Osborne
Timothy F
TF
Yanagisawa
Masashi
M
Yamamoto
Tokuo T
TT
Kodama
Tatsuhiko
T
Sakai
Juro
J
D000107:Acetylation; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D006609:High Mobility Group Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006946:Hyperinsulinism / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D008928:Mitochondria / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D055755:SOXD Transcription Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D002843:Chromatin; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D006609:High Mobility Group Proteins; D006657:Histones; D018398:Homeodomain Proteins; D007328:Insulin; D012333:RNA, Messenger; D012097:Repressor Proteins; D055755:SOXD Transcription Factors; C095939:Sox6 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D000255:Adenosine Triphosphate; D005947:Glucose