title: Inhibition of Small Maf Function in Pancreatic β-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion.
abstract: The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic β-cell function and maturation. However, insights about the effects of small Maf factors on β-cells are limited. Our goal was to elucidate the function of small-Maf factors on β-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with β-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of β-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates β-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve β-cell function.
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nomoto
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Takuma
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hida
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Arun J
authors.initials: AJ
authors.lastname: Sharma
authors.affiliation: Division of Rheumatology, Endocrinology and Nephrology (H.N., T.K., H.M., A.N., Y.H., T.A.), and Department of Transplant Surgery (K.Y.), Hokkaido University Graduate School of Medicine, Sapporo, Japan 060-8638; Section of Islet Transplantation and Cell Biology (A.J.S.), Joslin Diabetes Center, Boston, Massachusetts 02215; and MedImmune LLC (A.J.S.), Gaithersburg, Maryland 20878.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Atsumi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D059305:Diet, High-Fat; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051257:Proto-Oncogene Proteins c-maf / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D019076:Transgenes
chemical_list: D015415:Biomarkers; D007328:Insulin; C495608:Maf protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D005947:Glucose