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Extracellular matrix induced by TGFβ impairs insulin signal transduction in 3T3‐L1 preadipose cells
Author(s) -
Gag Anne Marie,
Chabot Josée,
Pardasani Dheerja,
Sorisky Alexander
Publication year - 1998
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/(sici)1097-4652(199806)175:3<370::aid-jcp15>3.0.co;2-9
Subject(s) - extracellular matrix , signal transduction , microbiology and biotechnology , transforming growth factor , extracellular , transduction (biophysics) , insulin , matrix (chemical analysis) , chemistry , medicine , endocrinology , biology , biochemistry , chromatography
When 3T3‐L1 preadipose cells are exposed to transforming growth factor β (TGFβ), they synthesize more extracellular matrix (ECM) and resist differentiation‐inducing stimuli. The mechanism by which ECM suppresses adipose cell differentiation (adipogenesis) remains unknown. Since adipogenesis is an insulin/insulin‐like growth factor‐1 (IGF‐1)‐dependent process, we investigated whether TGFβ‐induced ECM inhibits insulin signaling. When preadipose cells were pretreated overnight with TGFβ, we observed a 75% decrease in insulin‐stimulated tyrosine phosphorylation of insulin receptor substrate‐1 (IRS‐1) compared to that in control cells. Culturing 3T3‐L1 preadipose cells on fibronectin, a component of the ECM induced by TGFβ, also inhibited insulin‐dependent IRS‐1 tyrosine phosphorylation and adipogenesis, supporting a role for ECM in mediating TGFβ's inhibitory effect on insulin signaling. Since the insulin‐stimulated association of phosphoinositide (PI) 3‐kinase with IRS‐1 depends on IRS‐1 tyrosine phosphorylation, we measured the presence of the PI 3‐kinase 85 kDa regulatory subunit in anti‐IRS‐1 immunoprecipitates. Following insulin stimulation, PI 3‐kinase‐IRS‐1 association was reduced by 70% in TGFβ pretreated vs. control preadipose cells. However, insulin‐stimulated cellular production of PI(3,4,5)P3 was unaltered by TGFβ pretreatment. This suggests that IRS‐1‐associated p85‐type PI 3‐kinase may represent a particular subset of total cellular PI 3‐kinase that is specifically inhibited by TGFβ. Reduction of insulin‐stimulated association of IRS‐1 with p85‐type PI 3‐kinase by TGFβ may be one potential mechanism through which TGFβ blocks 3T3‐L1 adipose cell differentiation. J. Cell. Physiol. 175:370–378, 1998. © 1998 Wiley‐Liss, Inc.