1. Essential Role of Insulin Receptor Substrate 1 (IRS-1) and IRS-2 in Adipocyte Differentiation
- Author
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Junji Matsui, Yasuo Akanuma, Ryo Suzuki, Yasuo Terauchi, Atsuko Tsuchida, Takashi Kadowaki, Ryozo Nagai, Junji Kamon, Hiroshi Miki, Satoshi Kimura, Kajuro Komeda, Yasushi Kaburagi, Toshimasa Yamauchi, Naoto Kubota, and Kazuyuki Tobe
- Subjects
medicine.medical_specialty ,Peroxisome proliferator-activated receptor gamma ,White adipose tissue ,Biology ,Mice ,chemistry.chemical_compound ,Downregulation and upregulation ,Internal medicine ,Adipocyte ,Enhancer binding ,Adipocytes ,medicine ,Animals ,Receptor ,Cell Growth and Development ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,Lipoprotein lipase ,Intracellular Signaling Peptides and Proteins ,Cell Differentiation ,Cell Biology ,Phosphoproteins ,IRS1 ,Endocrinology ,chemistry ,Insulin Receptor Substrate Proteins - Abstract
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 2/2 ), IRS-2 deficient (IRS-2 2/2 ), and IRS-1 IRS-2 double deficient (IRS-1 2/2 IRS-2 2/2 ), from mouse embryos of the corresponding genotypes. The abilities of IRS-1 2/2 cells and IRS-2 2/2 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 2/2 IRS-2 2/2 cells have no ability to differentiate into adipocytes. The expression of CCAAT/enhancer binding protein a (C/EBPa) and peroxisome proliferator-activated receptor g (PPARg) is severely decreased in IRS-1 2/2 IRS-2 2/2 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 2/2 IRS-2 2/2 cells. Phosphatidylinositol 3-kinase (PI 3-kinase) activity that increases during adipocyte differentiation is almost completely abolished in IRS-1 2/2 IRS-2 2/2 cells. Treatment of wild-type cells with a PI 3-kinase inhibitor, LY294002, markedly decreases the expression of C/EBPa and PPARg, a result which is associated with a complete block of adipocyte differentiation. Moreover, histologic analysis of IRS-1 2/2 IRS-2 2/2 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/EBPa and PPARg expression and adipocyte differentiation. Recently there has been a dramatic increase in the prevalence of obesity attributable to excessive white adipose tissue both in Western countries and in Japan. Because adipocytes play a critical role in energy balance, understanding the molecular mechanisms of adipocyte differentiation may provide clues to strategies for the prevention and treatment of obesity. The mechanisms of adipocyte differentiation have been ex
- Published
- 2001
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