The protein kinase D1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats

摘要

Aims: Skeletal muscle insulin resistance (SMIR) contributes to the metabolic syndrome. Mounting evidence has demonstrated that the second generation antipsychotic olanzapine causes SMIR. The present study sought to investigate the molecular mechanisms underlying olanzapine-induced SMIR. @@@ Main methods: Male rats were given olanzapine (5 mg/kg, by a gavage method) for consecutive eight weeks. Plasma glucose and insulin concentrations were determined enzymatically or by ELISA. Gene/protein expression was analyzed by Real-Time PCR, Western blot and/or immunohistochemistry. @@@ Key findings: Olanzapine increased fasting plasma insulin concentration, and decreased glucose clearance during insulin tolerance test in rats. In skeletal muscle, it decreased protein expression of membrane glucose transporter (GLUT) 4, the ratio of membrane to total GLUT4, and total insulin receptor substrate 1 (IRS1). However, it increased protein phosphorylation of Ser(307) in IRS1, Y-607 in phosphoinositide 3-kinase p85 alpha and Ser(307) in AKT. These results indicate olanzapine-induced impairment of skeletal muscle insulin signaling. Mechanistically, olanzapine upregulated mRNA expression of TNF alpha, IL6 and IL1 beta, and protein phosphorylation of both I kappa B kinase (IKK)alpha/beta and nuclear factor (NF)kappa B p65. Furthermore, it increased protein phosphorylation of Ser(485/491) in AMPK alpha 2, whereas it decreased AMPK alpha 2 activity. More importantly, both Western blot and immunohistochemical analyses revealed that olanzapine increased protein phosphorylation of Ser(744/748) in protein kinase D1 (PKD1). @@@ Significance: The present results suggest that the PKD1-mediated inflammatory pathway is involved in olanzapine-induced impairment of skeletal muscle insulin signaling in rats. Our findings may go new insight into the mechanisms underlying olanzapine-induced SMIR.

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