Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin.
The insulin/IGF-1 (insulin-like growth factor 1) signalling pathway promotes adipocyte differentiation via complex signalling networks. Here, using microarray analysis of brown preadipocytes that are derived from wild-type and insulin receptor substrate (Irs) knockout animals that exhibit progressively impaired differentiation, we define 374 genes/expressed-sequence tags whose expression in preadipocytes correlates with the ultimate ability of the cells to differentiate. Many of these genes, including preadipocyte factor-1 (Pref-1) and multiple members of the Wnt signalling pathway, are related to early adipogenic events. Necdin is also markedly increased in Irs knockout cells that cannot differentiate, and knockdown of necdin restores brown adipogenesis with downregulation of Pref-1 and Wnt10a expression. Insulin receptor substrate proteins regulate a necdin-E2F4 interaction that represses peroxisome-proliferator-activated receptor gamma (PPARgamma) transcription via a cyclic AMP response element binding protein (CREB)-dependent pathway. Together these define a key signalling network that is involved in brown preadipocyte determination.
Tseng
Yu-Hua
YH
Research Division, Joslin Diabetes Center, Children's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Butte
Atul J
AJ
Kokkotou
Efi
E
Yechoor
Vijay K
VK
Taniguchi
Cullen M
CM
Kriauciunas
Kristina M
KM
Cypess
Aaron M
AM
Niinobe
Michio
M
Yoshikawa
Kazuaki
K
Patti
Mary Elizabeth
ME
Kahn
C Ronald
CR
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050704:E2F4 Transcription Factor; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins
D002135:Calcium-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C512925:Dlk1 protein, mouse; D050704:E2F4 Transcription Factor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D047495:PPAR gamma; D012097:Repressor Proteins; D014157:Transcription Factors; D051153:Wnt Proteins; C069766:necdin; D011972:Receptor, Insulin