Tumor necrosis factor-alpha causes insulin receptor substrate-2-mediated insulin resistance and inhibits insulin-induced adipogenesis in fetal brown adipocytes.
Treatment of fetal brown adipocytes with 0.6 nM tumor necrosis factor (TNF)-alpha 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-alpha. The antiadipogenic effect of TNF-alpha was accompanied by a down-regulation of CCAAT/enhancer-binding protein-alpha and beta mRNAs and up-regulation of CCAAT/enhancer-binding protein-delta, with the expression of peroxisome proliferator-activated receptor-gamma remaining essentially unmodified. Moreover, TNF-alpha caused an insulin resistance on the insulin-induced glucose uptake in brown adipocytes. Pretreatment with TNF-alpha 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-alpha 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 alpha-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-alpha induced an IRS-2- but not IRS-1-mediated insulin resistance on glucose transport and lipid synthesis in fetal brown adipocytes.
Valverde
A M
AM
Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Teruel
T
T
Navarro
P
P
Benito
M
M
Lorenzo
M
M
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D005260:Female; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000502:physiology; D009124:Muscle Proteins; D009687:Nuclear Proteins / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526299:Irs2 protein, rat; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; C495694:Slc2a4 protein, rat; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose