Chronic Tumor Necrosis Factor-α Treatment Causes Insulin Resistance via Insulin Receptor Substrate-1 Serine Phosphorylation and Suppressor of Cytokine Signaling-3 Induction in 3T3-L1 Adipocytes

Abstract

Serine phosphorylation of insulin receptor substrate (IRS)-1 and the induction of suppressor of cytokine signaling 3 (SOCS3) is recently well documented as the mechanisms for the insulin resistance. However, the relationship between these two mechanisms is not fully understood. In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFalpha-induced insulin resistance in 3T3-L1 adipocytes. TNFalpha transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNFalpha treatment longer than 4 h. These results suggest that serine phosphorylation of IRS-1 alone is not the major mechanism for the inhibited insulin signaling by TNFalpha. TNFalpha stimulation longer than 4 h enhanced the expression of SOCS3 and signal transducer and activator of transcription-3 phosphorylation, concomitantly with the production of IL-6. Anti-IL-6 neutralizing antibody ameliorated suppressed insulin signaling by 24 h TNFalpha treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription-3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNFalpha. However, low-level expression of SOCS3 by IL-6 or adenovirus vector did not affect insulin-stimulated IRS-1 tyrosine phosphorylation. Interestingly, when IRS-1 serine phosphorylation was enhanced by TNFalpha or anisomycin in the presence of low-level SOCS3, IRS-1 degradation was remarkably enhanced. Taken together, both IRS-1 serine phosphorylation and SOCS3 induction are necessary, but one of the pair is not sufficient for the inhibited insulin signaling. Chronic TNFalpha may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.

Mammalian target of the rapamycin pathway is involved in non-alcoholic fatty liver disease

“…TnFα is not only involved in inflammatory reactions, but also plays an important role in fat metabolism as an adipocytokine (30,31). TnFα may induce ir by impairing insulin sensitivity via inhibition of Pi3K activity, decreasing expression of glucose transporter 4 (GluT4) and downregulating PPar-α, adiponectin and irS-1 (31,32). in addition, il-6 is an important modulator for energy metabolism balance, and may significantly inhibit insulin-dependent activation of aKT and suppress the expression of irS-1, GluT4 and Pi3K, thereby affecting post-insulin receptor signaling and causing ir (31).…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…Indeed, TNF-␣ was demonstrated to interfere with insulin signaling in 316 ANDERSON AND BORLAK both dependent and independent fashions from IRS-1 (de Luca and Olefsky, 2008). Induction of suppressor of cytokine signaling 3 has been connected not only to inhibition of insulin signaling by IL-6 but also to that by TNF-␣ (Ishizuka et al, 2007). Insulin resistance may also mediated by other factors downstream of AKT/PI3K, which may be involved in impaired insulin signaling, such as structurally impaired cellular transport [e.g., of the insulin receptor (Inokuchi, 2006), GLUT4 transporter (Franck et al, 2007), and impaired lipid dynamics (i.e., defects or insufficiencies in lipid droplet (LD) associated proteins) (Kawanishi et al, 2000)].…”

Adenovirus infection results in alterations of insulin signaling and glucose homeostasis

“…We wished to study the mechanisms underlying this acute onset of insulin resistance after injury using Ad as a gene transfer tool to express proteins in vivo. Our initial studies included injection of a replication-deficient Ad vector, encoding ␤-Gal (Ad5-LacZ, 10 10 pfu) into rat via the tail vein. At 6 days after Ad5-LacZ injection, surgical trauma for 90 min (T90') was performed, a normal part of our surgical procedure.…”