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

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• 作者：Jina Kim^a ; Yu-Jin Lee^a ; ^b ; Jung Min Kim^a ; So Young Lee^a ; Myung-Ae Bae^c ; Jin Hee Ahn^c ; Dong Cho Han^a ; ^b ; Byoung-Mog Kwon^a ; ^b ; ^{kwonbm@kribb.re.kr}
• 关键词：PPAR ; peroxisome proliferator activated receptor ; FLD ; fatty liver dystrophy ; TAG ; triacylglycerol ; PAP ; phosphatidate phosphatase ; T2DM ; type-2 diabetes mellitus ; DAG ; diacylglycerol ; TZD ; thiazolidinedione ; RGZ ; rosiglitazone ; PGZ ; pioglitazone
• 刊名：The International Journal of Biochemistry & Cell Biology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：81
• 期：part_PA
• 页码：57-66
• 全文大小：3348 K
• 卷排序：81

文摘

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.