title: ISL1 regulates peroxisome proliferator-activated receptor γ activation and early adipogenesis via bone morphogenetic protein 4-dependent and -independent mechanisms.
abstract: While adipogenesis is controlled by a cascade of transcription factors, the global gene expression profiles in the early phase of adipogenesis are not well defined. Using microarray analysis of gene expression in 3T3-L1 cells, we have identified evidence for the activity of 2,568 genes during the early phase of adipocyte differentiation. One of these, the ISL1 gene, was of interest since its expression was markedly upregulated 1 h after initiation of differentiation, with a subsequent rapid decline. Overexpression of ISL1 at early times during adipocyte differentiation but not at later times was found to profoundly inhibit differentiation. This was accompanied by moderate downregulation of peroxisome proliferator-activated receptor γ (PPARγ) levels, substantial downregulation of PPARγ downstream genes, and downregulation of bone morphogenetic protein 4 (BMP4) levels in preadipocytes. Readdition of BMP4 overcame the inhibitory effect of ISL1 on the expression of PPARγ but not aP2, a gene downstream of PPARγ, and BMP4 also partially rescued ISL1 inhibition of adipogenesis, an effect which is additive with rosiglitazone. These results suggest that ISL1 is intimately involved in early regulation of adipogenesis, modulating PPARγ expression and activity via BMP4-dependent and -independent mechanisms. Our time course gene expression survey sets the stage for further studies to explore other early and immediate regulators.
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales, Australia School of Information Technologies, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Pengyi
authors.initials: P
authors.lastname: Yang
authors.affiliation: Peter Wills Bioinformatics Center, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Warren H
authors.initials: WH
authors.lastname: Kaplan
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Bon Hyang
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Wu
authors.affiliation: School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Jean Yee-Hwa
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Division of Molecular Biology, School of Life Sciences, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Yasunaga
authors.affiliation: Division of Molecular Biology, School of Life Sciences, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Sato
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Chisholm
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia Charles Perkins Centre Research and Education Hub, The University of Sydney, Sydney, New South Wales, Australia david.james@sydney.edu.au.
authors.forename: David E
authors.initials: DE
authors.lastname: James
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D060850:LIM-Homeodomain Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; D000077154:Rosiglitazone