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Tumor necrosis factor‐α and ceramides in insulin resistance
Author(s) -
Brindley David N.,
Wang ChuenNeu,
Mei Jie,
Xu James,
Hanna Atef N.
Publication year - 1999
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/bf02562240
Subject(s) - lipidology , clinical chemistry , insulin resistance , tumor necrosis factor alpha , tumor necrosis factor α , medicine , chemistry , endocrinology , insulin
The present studies tested the hypothesis that some effects of tumor necrosis factor‐α (TNF‐α) are mediated by activation of sphingomyelinases and the production of ceramides. Differentiated 3T3‐L1 adipocytes were incubated with short‐chain ceramide analogs, (C 2 ‐ and C 6 ‐ceramides: N ‐acetyl‐ and N ‐hexanoyl‐sphingosines, respectively), and this treatment increased 2‐deoxyglucose uptake in the absence of insulin progressively from 2–24 h. This effect was inhibited by blocking the activations of mitogen‐activated protein kinase, phosphatidylinositol 3‐kinase (PI 3‐kinase), and ribosomal S6 kinase which mediated an increase in GLUT1 concentrations. Long‐term increases in PI 3‐kinase activity associated with insulin receptor substrate‐1 (IRS‐1) increased the proportion of GLUT1 and GLUT4 in plasma membranes. These events explain the increases in noninsulin‐dependent glucose uptake and incorporation of this glucose into the fatty acid and glycerol moieties of triacylglycerol. The mechanisms by which TNF‐α and ceramides increase PI 3‐kinase activity were investigated further by using rat2 fibroblasts. Incubation for 20 min with TNF‐α, bacterial sphingomyelinase, or C 2 ‐ceramides increased PI 3‐kinase activity by about fivefold, and this effect depended upon a stimulation of tyrosine kinase activity and an increase in Ras‐GTP. This demonstrates the existence of a novel signaling pathway for TNF‐α that could contribute to the effects of this cytokine in stimulating basal glucose uptake. By contrast, treating the 3T3‐L1 adipocytes for 2–24 h with C 2 ‐ceramide diminished insulin‐stimulated glucose uptake by decreasing the insulin‐induced translocation of GLUT1 and GLUT4 to plasma membranes. This inhibition was observed when there was no increase in basal glucose uptake, and it occurred downstream of PI 3‐kinase. Our work provides further mechanisms whereby TNF‐α and ceramides produce insulin resistance and decrease the effectiveness of insulin in stimulating glucose disposal from the blood. Conversely, TNF‐α and ceramides increase the ability of adipocytes to take up glucose and store triacylglycerol in the absence of insulin.