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Causes Insulin Receptor Substrate-2-Mediated Insulin Resistance and Inhibits Insulin-Induced Adipogenesis in Fetal Brown Adipocytes1
Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain
Address all correspondence and requests for reprints to: Margarita Lorenzo, Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, 28040-Madrid, Spain. E-mail: mlorenzo{at}eucmax.sim.ucm.es
Treatment of fetal brown adipocytes with 0.6 nM tumor
necrosis factor (TNF)-
for 24 h resulted in a partial
impairment in the expression of fatty acid synthase,
glycerol-3-phosphate dehydrogenase, and glucose transporter (GLUT)-4
messenger RNAs (mRNAs), as well as in the enhancement in the
cytoplasmic lipid content in response to insulin. However, the
expression of the tissue-specific gene, uncoupling protein 1, is
increased by the presence of TNF-. The antiadipogenic effect of
TNF- was accompanied by a down-regulation of CCAAT/enhancer-binding
protein- and ß mRNAs and up-regulation of CCAAT/enhancer-binding
protein-
, with the expression of peroxisome proliferator-activated
receptor-
remaining essentially unmodified. Moreover, TNF- caused
an insulin resistance on the insulin-induced glucose uptake in brown
adipocytes. Pretreatment with TNF- resulted in hypophosphorylation
of the insulin receptor in response to insulin, without affecting the
number of insulin receptors per cell or its molecular mass. However,
insulin receptor substrate (IRS)-1 and IRS-2 signaling in response to
insulin showed functional differences. Thus, TNF- pretreatment
induced a hypophosphorylation of IRS-2 but not of IRS-1. This effect
leads to an impairment in the IRS-2-associated phosphatidylinositol
(PI) 3-kinase activation due to a decreased association of -p85
regulatory subunit of PI 3-kinase with IRS-2 but not in the
IRS-1-associated PI 3-kinase activation in response to insulin. Our
results indicate that TNF- induced an IRS-2- but not IRS-1-mediated
insulin resistance on glucose transport and lipid synthesis in fetal
brown adipocytes.
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