Journal article

Publication year: 2001

Pages: 319-329

Journal: Molecular and Cellular Biology

Volume number: 21

Issue number: 1

ISSN: 0270-7306

DOI Link: https://doi.org/10.1128/MCB.21.1.319-329.2001

Publisher: Taylor and Francis Group

Abstract: 
The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin, To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPAR gamma), CCAAT/enhancer-binding protein alpha (C/EBP alpha), fatty acid synthase, uncoupling protein-1, and glucose transporter 4, The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPAR gamma, or C/EBP alpha but not the thiazolidinedione troglitazone, Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS3. Akt phosphorylation was reduced in parallel with the total PI 3-kinase activity. Inhibition of PI 3-kinase with LY294002 blocked differentiation of mild-type cells, Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPAR gamma and C/EBP alpha.

Harvard Citation style: Fasshauer, M., Klein, J., Kriauciunas, K., Ueki, K., Benito, M. and Kahn, C. (2001) Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes, Molecular and Cellular Biology, 21(1), pp. 319-329. https://doi.org/10.1128/MCB.21.1.319-329.2001

APA Citation style: Fasshauer, M., Klein, J., Kriauciunas, K., Ueki, K., Benito, M., & Kahn, C. (2001). Essential role of insulin receptor substrate 1 in differentiation of brown adipocytes. Molecular and Cellular Biology. 21(1), 319-329. https://doi.org/10.1128/MCB.21.1.319-329.2001