TY - JOUR
T1 - Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation
AU - Miki, H.
AU - Yamauchi, T.
AU - Suzuki, R.
AU - Komeda, K.
AU - Tsuchida, A.
AU - Kubota, N.
AU - Terauchi, Y.
AU - Kamon, J.
AU - Kaburagi, Y.
AU - Matsui, J.
AU - Akanuma, Y.
AU - Nagai, R.
AU - Kimura, S.
AU - Tobe, K.
AU - Kadowaki, T.
PY - 2001
Y1 - 2001
N2 - To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1-/-), IRS-2 deficient (IRS-2-/-), and IRS-1 IRS-2 double deficient (IRS-1-/- IRS-2-/-), from mouse embryos of the corresponding genotypes. The abilities of IRS-1-/- cells and IRS-2-/- cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1-/- IRS-2-/- cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) is severely decreased in IRS-1-/- IRS-2-/- cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1-/- IRS-2-/- cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1-/- IRS-2-/- cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPα and PPARγ a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1-/- IRS-2-/- double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPα and PPARγ expression and adipocyte differentiation.
AB - To investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, the two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1-/-), IRS-2 deficient (IRS-2-/-), and IRS-1 IRS-2 double deficient (IRS-1-/- IRS-2-/-), from mouse embryos of the corresponding genotypes. The abilities of IRS-1-/- cells and IRS-2-/- cells to differentiate into adipocytes are approximately 60 and 15%, respectively, lower than that of wild-type cells, at day 8 after induction and, surprisingly, IRS-1-/- IRS-2-/- cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) is severely decreased in IRS-1-/- IRS-2-/- cells at both the mRNA and the protein level, and the mRNAs of lipoprotein lipase and adipocyte fatty acid binding protein are severely decreased in IRS-1-/- IRS-2-/- cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1-/- IRS-2-/- cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPα and PPARγ a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1-/- IRS-2-/- double-knockout mice 8 h after birth reveals severe reduction in white adipose tissue mass. Our results suggest that IRS-1 and IRS-2 play a crucial role in the upregulation of the C/EBPα and PPARγ expression and adipocyte differentiation.
UR - http://www.scopus.com/inward/record.url?scp=0035099508&partnerID=8YFLogxK
U2 - 10.1128/MCB.21.7.2521-2532.2001
DO - 10.1128/MCB.21.7.2521-2532.2001
M3 - 学術論文
C2 - 11259600
AN - SCOPUS:0035099508
SN - 0270-7306
VL - 21
SP - 2521
EP - 2532
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 7
ER -