Treatment with IFN‐γ prevents insulin‐dependent PKB, p70^S6k phosphorylation and protein synthesis in mouse C2C12 myogenic cells

Abstract

The purpose of the present study was to examine the potential effect of IFN-gamma (interferon-gamma) on the cellular content and phosphorylation of PKB (protein kinase B), p70S6k (p70 S6 kinase) and MAPK (mitogen-activated protein kinase), and on the ability of insulin to stimulate the glucose uptake and protein synthesis in mouse C2C12 myotubes. Insulin (100 nmol/l) stimulated glucose uptake in C2C12 myotubes by 203.4%. Glucose uptake in cells differentiated in the presence of IFN-gamma (10 ng/ml) was increased by 165.8% and was not further significantly modified by the addition of insulin (183.4% of control value). Insulin increased the rate of protein synthesis by 198.8%. The basal rate of protein synthesis was not affected by IFN-gamma; however, this cytokine abolished the insulin effect. Cellular levels of PKB, p70S6k, p42MAPK and p44MAPK were not modified by IFN-gamma. Insulin caused the phosphorylation of PKB and the activation of p70S6k, but not p42MAPK and p44MAPK. In cells differentiated in the presence of IFN-gamma, the insulin-mediated PKB phosphorylation was significantly diminished, whereas the phosphorylation of p70S6k was completely prevented. Pretreatment of C2C12 myogenic cells with IFN-gamma led to the marked increase in p42MAPK phosphorylation. Exposure of C2C12 myoblasts to IFN-gamma impaired MyoD and myogenin expression and decreased the fusion index on the fifth day of differentiation. In conclusion, (i) IFN-gamma present in the extracellular environment during C2C12 myoblast differentiation prevents the stimulatory action of insulin on protein synthesis; (ii) IFN-gamma-induced insulin resistance of protein synthesis in myogenic cells can be associated with the decreased phosphorylation of PKB and p70S6k, as well as with the augmented basal phosphorylation of p42MAPK; (iii) this cytokine effect can be partly explained by alterations in the differentiation process.

Virus-Induced Interferon-γ Causes Insulin Resistance in Skeletal Muscle and Derails Glycemic Control in Obesity

“…Moreover, we have demonstrated in vivo that IFN-g is able to induce IR directly in non-immune cells. In vitro, IFN-g had been shown to cause IR in 3T3-L1 adipocytes and myoblasts by inhibiting insulin receptor signaling through induction of suppressor of cytokine signaling (SOCS) molecules (Grzelkowska-Kowalczyk and Wieteska-Skrzeczy nska, 2009;McGillicuddy et al, 2009;Wada et al, 2011). We show that in vivo IFN-g specifically reduced glucose uptake in skeletal muscle by downregulation of the insulin receptor.…”

Lack of Oncostatin M Receptor β Leads to Adipose Tissue Inflammation and Insulin Resistance by Switching Macrophage Phenotype

“…In the present study, the IL-6 levels did not change in the adipose tissue of OSMR␤ Ϫ/Ϫ mice compared with those observed in the controls at 16 weeks of age when systemic insulin resistance developed in OSMR␤ Ϫ/Ϫ mice. By contrast, some proinflammatory cytokines (TNF-␣, IL-1␤, and IFN-␥), known to contribute to the development of insulin resistance (16,17,(37)(38)(39)(40), was significantly increased in the adipose tissue of OSMR␤ Ϫ/Ϫ mice. Therefore, IL-6 may function in the development of adipose tissue inflammation and insulin resistance in a manner distinct from that exhibited by other proinflammatory cytokines, including TNF-␣, IL-1␤, and IFN-␥.…”

“…It is well established that the balance between pro-and antiinflammatory cytokines secreted from the adipose tissue is important for systemic insulin sensitivity. Proinflammatory cytokines, including TNF-␣, IL-1␤, and IFN-␥, promote the development of insulin resistance (16,17,(37)(38)(39)(40), whereas an anti-inflammatory cytokine, IL-10, improves obesity-induced insulin resistance (18). In the adipose tissue, these pro-and anti-inflammatory cytokines are produced by M1 and M2 macrophages, respectively (15).…”

Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: A vicious circle of clinical significance?

“…IFN-c-mediated loss of insulin-stimulated glucose uptake in human adipocytes was coincident with reduced Akt/PKB phosphorylation and down-regulation of the IR, IRS-1, and GLUT4 that was mediated via sustained JAK-STAT1 pathway activation. 53,54 It is not known if a mechanism by which IFN-a interferes with insulin signaling in liver cells is similar to the ones described for IFN-c in other cell types; however, the shared use of the IRS signaling pathway raises the possibility that the antagonism of IFN-a on insulin signaling could occur through the common use of proteins in the IRS signaling system (IRS-1 in particular) (Fig. 8B).…”