PPARγ agonists induce adipocyte differentiation by modulating the expression of Lipin-1, which acts as a PPARγ phosphatase

PPAR gamma agonists induced obesity in animal models as a side effect. Microarray experiments reveal that PPAR gamma agonist upregulates the expression of lipin-1 and this upregulation is correlated with the activity of the agonists. Lipin-1 induced by PPAR gamma agonists decreased the levels of PPAR gamma and ERK1/2 phosphorylation through direct interaction with these proteins in 3T3-L1 cells. In PPAR gamma agonist-treated 3T3-L1 preadipocytes, the knockdown of lipin-1 expression by small interfering RNA inhibited the adipogenesis that was induced by PPAR gamma agonists. In contrast, PPAR gamma 2 expression was increased, and lipid droplets were accumulated in lipin-l-overexpressing 3T3-L1 adipocytes. Rosiglitazone (RGZ), a strong PPAR gamma agonist, synergistically promoted PPAR gamma dephosphorylation and adipogenesis in lipin-l-overexpressing 3T3-L1 preadipocytes. Therefore, lipin-1 has dual functions as a transcriptional cofactor and phosphatidate phosphatase (PAP) in the differentiation of preadipocyte cells induced by strong PPAR gamma agonists. In addition, the adipogenesis of 3T3-L1 cells was markedly upregulated by diacylglycerol (DAG), which was produced by lipin-1. Therefore, lipin-1 induction by PPAR gamma agonists might be an important factor in understanding the biological mechanism of the agonists' adverse effects, and this information may be valuable in the development of type-2 diabetes mellitus (T2DM) therapeutics with reduced adverse effects and greater tolerability. (C) 2016 Elsevier Ltd. All rights reserved.