An extract of Urtica dioica L. mitigates obesity induced insulin resistance in mice skeletal muscle via protein phosphatase 2A (PP2A).

Diana N Obanda,Jacqueline Stephens,Yongmei Yu,William T Cefalu,David Ribnicky

doi:10.1038/srep22222

Abstract

The leaf extract of Urtica dioica L. (UT) has been reported to improve glucose homeostasis in vivo, but definitive studies on efficacy and mechanism of action are lacking. We investigated the effects of UT on obesity- induced insulin resistance in skeletal muscle. Male C57BL/6J mice were divided into three groups: low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with UT. Body weight, body composition, plasma glucose and plasma insulin were monitored. Skeletal muscle (gastrocnemius) was analyzed for insulin sensitivity, ceramide accumulation and the post translational modification and activity of protein phosphatase 2A (PP2A). PP2A is activated by ceramides and dephosphorylates Akt. C2C12 myotubes exposed to excess free fatty acids with or without UT were also evaluated for insulin signaling and modulation of PP2A. The HFD induced insulin resistance, increased fasting plasma glucose, enhanced ceramide accumulation and PP2A activity in skeletal muscle. Supplementation with UT improved plasma glucose homeostasis and enhanced skeletal muscle insulin sensitivity without affecting body weight and body composition. In myotubes, UT attenuated the ability of FFAs to induce insulin resistance and PP2A hyperactivity without affecting ceramide accumulation and PP2A expression. UT decreased PP2A activity through posttranslational modification that was accompanied by a reduction in Akt dephosphorylation.

Highlights

Obesity induced insulin resistance is a key pathophysiologic feature of type 2 diabetes mellitus (T2DM)
Based on previous reports that have demonstrated that phosphatase 2A (PP2A) inhibition with okadaic acid or a neutralizing antibody increased Akt activity[14,15,16,17], we determined the effect of Urtica dioica L. (UT) on the activity of PP2A
We report the effects of a UT extract on plasma glucose homeostasis and insulin signaling in skeletal muscle tissues from mice fed a high-fat diet

Summary

Introduction

Obesity induced insulin resistance is a key pathophysiologic feature of type 2 diabetes mellitus (T2DM). We hypothesized that UT maintains insulin sensitivity through mechanisms that enhance Akt phosphorylation despite the accumulation of ceramides in skeletal muscle. Our observations from two model systems that include in vitro and in vivo studies demonstrate that supplementation with UT attenuates lipid induced PP2A hyperactivity and enhances insulin sensitivity and insulin stimulated glucose metabolism in skeletal muscle. These studies strongly suggest that UT has metabolically beneficial effects in skeletal muscle and indicate its potential as a botanical supplement for metabolic disease states such as insulin resistance

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