title: The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss.
abstract: BACKGROUND
  Adipose tissue is critical for systemic metabolic health. Identifying key factors regulating adipose tissue function 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 and muscle. However, the expression of the NR4A members in human adipose tissue has not previously been described, and their target genes are largely unknown.
  
  
  OBJECTIVE
  To determine whether the NR4As are differentially expressed in human adipose tissue in obesity, and identify potential NR4A target genes.
  
  
  METHODS
  Prospective analysis of s.c. adipose tissue before and 1 year after fat loss, and during in vitro differentiation of primary human preadipocytes. Case-control comparison of omental (OM) adipose tissue.
  
  
  METHODS
  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 or laparotomy were included in the study. Measurements were done by quantitative PCR gene expression analysis of the NR4A members 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 were expressed at the highest level in stromal-vascular fraction compared with adipocytes, but were downregulated in both fractions 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 strongly induced within 30 min of tissue incubation. Finally, promoter analysis revealed potential NR4A target genes involved in stress response, immune response, development and other functions. Our data show altered adipose tissue expression of the NR4As in obesity, suggesting that these stress responsive nuclear receptors may modulate pathogenic potential in humans.
authors.affiliation: Institute of Medicine, University of Bergen, Bergen, Norway.
authors.forename: V L
authors.initials: VL
authors.lastname: Veum
authors.forename: S N
authors.initials: SN
authors.lastname: Dankel
authors.forename: J
authors.initials: J
authors.lastname: Gjerde
authors.forename: H J
authors.initials: HJ
authors.lastname: Nielsen
authors.forename: M H
authors.initials: MH
authors.lastname: Solsvik
authors.forename: C
authors.initials: C
authors.lastname: Haugen
authors.forename: B J
authors.initials: BJ
authors.lastname: Christensen
authors.forename: T
authors.initials: T
authors.lastname: Hoang
authors.forename: D J
authors.initials: DJ
authors.lastname: Fadnes
authors.forename: C
authors.initials: C
authors.lastname: Busch
authors.forename: V
authors.initials: V
authors.lastname: Våge
authors.forename: J V
authors.initials: JV
authors.lastname: Sagen
authors.forename: G
authors.initials: G
authors.lastname: Mellgren
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009664:Norway; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D009767:Obesity, Morbid / Q000378:metabolism* / Q000601:surgery; D011446:Prospective Studies; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D015854:Up-Regulation; D015431:Weight Loss / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; C490412:NR4A3 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors