Asymmetrical dimethylarginine triggers lipolysis and inflammatory response via induction of endoplasmic reticulum stress in cultured adipocytes.

Protein energy wasting, a state of decreased stores of body protein and fat, is a risk factor for mortality in advanced chronic kidney disease (CKD). Little is known about the mechanism underlying loss of fat in CKD. Accumulation of asymmetric dimethylarginine (ADMA) is prevalent in advanced CKD. Here we assessed the effect of ADMA on cellular perturbation in cultured 3T3-L1 adipocytes. Exposure of adipocytes to ADMA induced lipolysis and decreased perilipin A, with no alteration of lipases expression or activity. ADMA treatment also upregulated the expression of inflammatory adipocytokines via activation of nuclear factor-kappaB (NF-kappaB). Blocking the inflammatory responses with NF-kappaB inhibitor partly inhibited the ADMA-induced lipolysis. Furthermore, ADMA treatment triggered endoplasmic reticulum (ER) stress, revealed by phosphorylation of PKR-like eukaryotic initiation factor 2alpha kinase, eukaryotic translational initiation factor 2alpha, c-Jun NH2-terminal kinase, and overexpression of glucose-regulated protein 78. Treatment with ER stress inhibitor completely abolished the ADMA-induced lipolysis and inflammatory responses. Moreover, conditioned medium from the ADMA-treated adipocytes increased protein degradation in cultured C2C12 myotubes, suggesting that the ADMA-induced adipocyte perturbation may promote skeletal muscle proteolysis. These data suggest that elevated ADMA promoted the adipocyte perturbation through induction of ER stress, which might have implication for protein energy wasting in CKD.