PKC-θ knockout mice are protected from fat-induced insulin resistance

Abstract

Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C-θ (PKC-θ), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-θ are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-θ KO mice following saline infusion. A 5-hour lipid infusion decreased insulinstimulated skeletal muscle glucose uptake in the WT mice that was associated with 40-50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated PI3K activity. In contrast, PKC-θ inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-θ is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-θ is a potential therapeutic target for the treatment of type 2 diabetes.

Lipid signalling in disease

“…Fatty acid metabolites such as fatty acid coenzyme A and DAG can activate PKC in muscles or PKC in the liver and inhibit insulin action 49,77 . Mice that are deficient in PKC are protected against fatty acid-induced insulin resistance, which confirms the contribution of this kinase to metabolic regulation in vivo 91 . At a mechanistic level, PKC is known to activate IKK and might contribute to insulin resistance through this pathway.…”

“…PKC is the third important mediator between metabolic pathways and the inflammatory response 49,77,91 . Fatty acid metabolites such as fatty acid coenzyme A and DAG can activate PKC in muscles or PKC in the liver and inhibit insulin action 49,77 .…”

Reduced AMP-activated protein kinase activity in mouse skeletal muscle does not exacerbate the development of insulin resistance with obesity

“…The combination of inflammation and accumulation of bioactive lipids is hypothesised to antagonise insulin signalling and insulin-stimulated glucose uptake by activating c-jun Nterminal kinase [3], inhibitory kappa beta kinase [4], protein kinase C theta [5] and protein phosphatase 2A [6].…”

Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance

“…Diacylglycerol is known to act as a second messenger for many signal transduction pathways, including the novel protein kinase C (PKC) family. PKC δ [27] and PKC θ [28] have been implicated in diacylglycerol-induced insulin resistance. Accordingly, we measured levels of these proteins in the liver and skeletal muscle of Il6 −/− and control mice.…”