NR4A1 retards adipocyte differentiation or maturation via enhancing GATA2 and p53 expression

Abstract

Nuclear receptor subfamily 4 group A member 1 (NR4A1) is an orphan nuclear receptor with diverse functions. It has been reported that NR4A1, as a transcriptional activator, is implicated in glucose and lipid metabolism. The aim of this study was to investigate the regulatory role of NR4A1 in adipogenesis and explore the underlying mechanisms. Quantitative real‐time PCR and Western blotting were used to analyse the expression of genes involved in synthesis and mobilization of fats in vivo and in vitro. Dual‐luciferase reporter assay was conducted to study the regulatory mechanisms of NR4A1. Our data from in vivo study confirmed that NR4A1 knockout (KO) mice fed with high‐fat diet were more prone to obesity, and gene expression levels of PPARγ and FAS were increased in KO mice compared to controls; our data from in vitro study showed that NR4A1 overexpression in 3T3‐L1 pre‐adipocytes inhibited adipogenesis. Moreover, NR4A1 enhanced GATA binding protein 2 (GATA2) expression, which in turn inhibited peroxisome proliferator‐activated receptor γ (PPARγ); NR4A1 inhibited sterol regulatory element binding transcription factor 1 (SREBP1) and its downstream gene fatty acid synthase (FAS) by up‐regulating p53. NR4A1 inhibits the differentiation and lipid accumulation of adipocytes by enhancing the expression of GATA2 and p53.

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

“…Nr4a3 results in similar changes in glucose metabolism gene expression. Muscle specific Nr4a3 overexpression mice fed a control diet presented with decreased epididymal, inguinal, brown and total adipose mass [169]. This corresponded with significantly lower circulating leptin levels.…”

“…This corresponded with significantly lower circulating leptin levels. When these mice were fed a high fat diet, the animals had decreased weight gain, adipose mass and circulating blood glucose [169]. Significant upregulation of glycolytic genes in the Nr4a3 overexpressing muscle was observed, including induction of HK1, Pfk-1, GAPDH, Pgam2, Eno3 and Pkm [169].…”

“…When these mice were fed a high fat diet, the animals had decreased weight gain, adipose mass and circulating blood glucose [169]. Significant upregulation of glycolytic genes in the Nr4a3 overexpressing muscle was observed, including induction of HK1, Pfk-1, GAPDH, Pgam2, Eno3 and Pkm [169]. In addition, components of the malate aspartate shuttle, including MDH and AST, were upregulated, as was Pdh, with downregulation of the glycerol phosphate shuttle and decreased NAD+/NADH ratio, indicative of more efficient ATP production [169].…”

Adipose‐derived mesenchymal stem cells differentiate into pancreatic cancer‐associated fibroblasts in vitro

“…Recent studies have suggested that CAFs were derived from MSCs, which may be either populated in the pancreas or recruited by neoplastic cells [7,30]. Whereas pancreatic stellate cells from mice or from human patients were used in previous studies [31,32], they were unstable and quite variable, as their characteristics were not accurately assessed.…”

The regulation of NR4A1 on glucolipid metabolism

“…GATA2表达来抑制PPARγ的转录表达, 并且通过间接 上调P53来降低SREBP1c以及下游基因FAS的表达, 从 而抑制脂肪细胞成熟和脂肪生成 [69] . 多数研究表明, NR4A1对脂肪的生成具有抑制作用 [66,67] , 但其中具体…”