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Gene-Expression Profiles in IRS Knockout Brown Preadipocytes

ABSTRACT: Insulin and IGF-1 promote adipocyte differentiation via complex and overlapping signalling networks. Here we used microarray analysis of brown preadipocytes derived from wild-type and insulin receptor substrate (IRS) knockout (KO) animals, which exhibited progressively impaired differentiation, to define the set of genes that predict adipogenic potential in these cells. 374 genes/ESTs were identified whose expression in preadipocytes correlated with their ultimate ability to differentiate. Many of these genes were related to early adipogenic events, including genes involved in extracellular matrix, cytoskeletal organization, growth arrest, post-mitotic clonal expansion, and inhibitors of adipogenesis, including preadipocyte factor-1 and multiple members of the Wnt-signalling pathway. Reconstitution of IRS-1 KO cells with IRS-1 reversed these changes and restored the ability to differentiate. Several of these genes showed concordant changes in brown adipose tissue in vivo. Necdin was markedly increased in IRS-1 KO cells that could not differentiate, and knockdown of necdin restored brown adipogenesis with down-regulation of Pref-1 and Wnt10a expression. We demonstrated a necdin-E2F4 interaction repressing PPARg transcription. IRS proteins regulated necdin via a CREB dependent pathway, defining a signalling network involved in brown preadipocyte determination. Keywords = brown fat Keywords = preadipocyte Keywords = adipogenesis Keywords = mouse Keywords: parallel sample

ORGANISM(S): Mus musculus

PROVIDER: GSE2556 | GEO | 2005/06/01

SECONDARY ACCESSION(S): PRJNA92167

REPOSITORIES: GEO

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Transcription profiling of preadipocytes of wild type and IRS-1,IRS-2, IRS-3, IRS-4 knock out mice to reveal role of insulin receptor substrates and necdin

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