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

• Published in: The international journal of biochemistry & cell biology Vol. 81; no. Pt A; pp. 57 - 66
• Main Authors: Kim, Jina, Lee, Yu-Jin, Kim, Jung Min, Lee, So Young, Bae, Myung-Ae, Ahn, Jin Hee, Han, Dong Cho, Kwon, Byoung-Mog
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.12.2016
• Subjects: 3T3-L1 Cells; Adipocytes; Adipocytes - cytology; Adipocytes - drug effects; Adipogenesis - drug effects; Animals; Cell Differentiation - drug effects; Diglycerides - metabolism; Gene Expression Regulation, Enzymologic - drug effects; Lipin-1; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Nuclear Proteins - genetics; Obesity; Phosphatase; Phosphatidate Phosphatase - genetics; Phosphorylation - drug effects; PPAR gamma - agonists; PPARγ; PPARγ agonists; Thiazolidinediones - pharmacology; T2DM; Obesity; PGZ; RGZ; DAG; Adipocytes; Phosphatase; PPARγ; PPAR; PPARγ agonists; TAG; PAP; Lipin-1; FLD; TZD
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2016.10.018

[Display omitted] PPARγ agonists induced obesity in animal models as a side effect. Microarray experiments reveal that PPARγ agonist upregulates the expression of lipin-1 and this upregulation is correlated with the activity of the agonists. Lipin-1 induced by PPARγ agonists decreased the levels of PPARγ and ERK1/2 phosphorylation through direct interaction with these proteins in 3T3-L1 cells. In PPARγ agonist-treated 3T3-L1 preadipocytes, the knockdown of lipin-1 expression by small interfering RNA inhibited the adipogenesis that was induced by PPARγ agonists. In contrast, PPARγ2 expression was increased, and lipid droplets were accumulated in lipin-1-overexpressing 3T3-L1 adipocytes. Rosiglitazone (RGZ), a strong PPARγ agonist, synergistically promoted PPARγ dephosphorylation and adipogenesis in lipin-1-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 PPARγ 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 PPARγ 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.