The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss

BACKGROUND: Adipose tissue is critical for systemic metabolic health. Identifying key factors regulating adipose tissuefunction is a research priority. The NR4A subfamily of nuclear receptors (NRs) (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1)has emerged as important proteins in different disease states and in the regulation of metabolic tissues, particularly in liver andmuscle. However, the expression of the NR4A members in human adipose tissue has not previously been described, and theirtarget genes are largely unknown.OBJECTIVE: To determine whether the NR4As are differentially expressed in human adipose tissue in obesity, and identifypotential NR4A target genes.DESIGN: Prospective analysis of s.c. adipose tissue before and 1 year after fat loss, and during in vitro differentiation of primaryhuman preadipocytes. Case-control comparison of omental (OM) adipose tissue.SUBJECTS: A total of 13 extremely obese patients undergoing biliopancreatic diversion with duodenal switch for fat loss,12 extremely obese patients undergoing laparoscopic sleeve gastrectomy and 37 lean individuals undergoing hernia repair orlaparotomy were included in the study. Measurements were done by quantitative PCR gene expression analysis of the NR4Amembers and in silico promoter analysis based on microarray data.RESULTS: There was a strong upregulation of the NR4As in extreme obesity and normalization after fat loss. The NR4As wereexpressed at the highest level in stromal--vascular fraction compared with adipocytes, but were downregulated in bothfractions after fat loss. Their expression levels were also significantly higher in OM compared with s.c. adipocytes in obesity.The NR4As were downregulated during differentiation of primary human preadipocytes. Moreover, the NR4As were stronglyinduced within 30min of tissue incubation. Finally, promoter analysis revealed potential NR4A target genes involved in stressresponse, immune response, development and other functions. Our data show altered adipose tissue expression of the NR4Asin obesity, suggesting that these stress responsive nuclear receptors may modulate pathogenic potential in humans.International Journal of Obesity (2012) 36, 1195--1202; doi:10.1038/ijo.2011.240; published online 6 December 2011Keywords: nuclear receptors; adipose tissue; stromal--vascular fraction; gene expressionINTRODUCTIONAdipose tissue, skeletal muscle and the liver are importantmetabolic organs and targets for metabolic therapies. Insulinresistance is a key component of metabolic disorders, anddevelopment of insulin resistance and systemic metabolicdysregulation may largely result from an altered function of theadipose tissue, particularly in the intraabdominal compartment.