Stinging Nettle (Urtica dioica L.) Attenuates FFA Induced Ceramide Accumulation in 3T3-L1 Adipocytes in an Adiponectin Dependent Manner.

Diana N Obanda,Jacqueline M Stephens,David Ribnicky,Peng Zhao,Allison J Richard,William T Cefalu,Herve Le Stunff

doi:10.1371/journal.pone.0150252

Abstract

ObjectiveExcess dietary lipids result in the accumulation of lipid metabolites including ceramides that can attenuate insulin signaling. There is evidence that a botanical extract of Urtica dioica L. (stinging nettle) improves insulin action, yet the precise mechanism(s) are not known. Hence, we examined the effects of Urtica dioica L. (UT) on adipocytes.Research DesignWe investigated the effects of an ethanolic extract of UT on free fatty acid (palmitic acid) induced inhibition of insulin-stimulated Akt serine phosphorylation and modulation of ceramidase expression in 3T3-L1 adipocytes. Adipocytes were exposed to excess FFAs in the presence or absence of UT. Effects on adiponectin expression, ceramidase expression, ceramidase activity, ceramide accumulation and insulin signaling were determined.ResultsAs expected, FFAs reduced adiponectin expression and increased the expression of ceramidase enzymes but not their activity. FFA also induced the accumulation of ceramides and reduced insulin-stimulated phosphorylation of Akt in adipocytes. The effects of FFA were partially reversed by UT. UT enhanced adiponectin expression and ceramidase activity in the presence of excess FFAs. UT abated ceramide accumulation and increased insulin sensitivity via enhanced Akt phosphorylation. A siRNA knockdown of adiponectin expression prevented UT from exerting positive effects on ceramidase activity but not Akt phosphorylation.ConclusionsIn adipocytes, the ability of UT to antagonize the negative effects of FFA by modulating ceramidase activity and ceramide accumulation is dependent on the presence of adiponectin. However, the ability of UT to enhance Akt phosphorylation is independent of adiponectin expression. These studies demonstrate direct effects of UT on adipocytes and suggest this botanical extract is metabolically beneficial.

Highlights

Insulin resistance in skeletal muscle, liver and adipose tissue is strongly associated with metabolites that result from lipid oversupply in obesity
The ability of Urtica dioica L. (UT) to antagonize the negative effects of FFA by modulating ceramidase activity and ceramide accumulation is dependent on the presence of adiponectin
The ability of UT to enhance Akt phosphorylation is independent of adiponectin expression

Summary

Introduction

Insulin resistance in skeletal muscle, liver and adipose tissue is strongly associated with metabolites that result from lipid oversupply in obesity. Plants have traditionally been a rich source of medicinal compounds for many conditions, including metformin as a treatment for diabetes. The single-stemmed perennial, has a long history of use as a folk medicine and as a food source in several Asian and North African cultures and in Latin America. In some cultures it is used as a food supplement or salad ingredient without reported side effects [5, 6]. The blood glucose lowering effects of Urtica dioica as a medicinal plant has been documented and reviewed [6]. The beneficial effects of UT include anti-hyperglycemic effects in glucose tolerance tests [7,8,9], enhancement of islet insulin secretion [10] and anti-inflammatory effects [11]

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