title: Adipocyte-derived products induce the transcription of the StAR promoter and stimulate aldosterone and cortisol secretion from adrenocortical cells through the Wnt-signaling pathway.
abstract: BACKGROUND
  Obesity is associated with hypersecretion of cortisol and aldosterone and a high prevalence of arterial hypertension. At the cellular level, a direct effect of adipocytes on the expression of the steroidogenic acute regulatory (StAR) protein, a regulator of cortisol and aldosterone synthesis, and on aldosterone and cortisol secretion has been shown. However, the molecular mechanisms mediating this effect are not known.
  
  
  OBJECTIVE
  Wnt-signaling molecules are secreted by adipocytes and regulate the activity of SF-1, a key transcription factor in adrenal steroidogenesis. Therefore, we investigated whether adipocytes stimulate adrenal steroidogenesis through the activation of Wnt-signaling.
  
  
  RESULTS
  Using immunohistochemistry, we detected the expression of frizzled and beta-catenin in the adult human adrenal cortex. Transient transfection of a Wnt-dependent reporter-gene into adrenal NCI-H295R cells showed an induction of Wnt-mediated transcription to 308% after treatment with human fat cell-conditioned medium (FCCM). This finding was paralleled by an induction of StAR promoter activity (420%) by FCCM. The induction of StAR promoter activity by FCCM was inhibited by 49% when Wnt-signaling was blocked by the soluble Wnt-antagonist secreted Frizzled-Related-Protein-1 (sFRP-1). Overexpression of a constitutively active mutant of beta-catenin induced the transcription of the StAR promoter (440%). beta-Catenin and FCCM induced SF-1-mediated transcription at a SF-1-driven reporter gene (420 and 402%, respectively). Furthermore, the secretion of aldosterone and cortisol by NCI-H295R cells induced by FCCM was significantly inhibited by the Wnt-antagonist sFRP-1.
  
  
  CONCLUSIONS
  These data indicate that the Wnt-signaling pathway is one of the mechanisms mediating the effects of fat cells on adrenal StAR transcription and aldosterone and cortisol secretion.
authors.affiliation: Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany. sven.schinner@uni-duesseldorf.de
authors.forename: S
authors.initials: S
authors.lastname: Schinner
authors.forename: H S
authors.initials: HS
authors.lastname: Willenberg
authors.forename: D
authors.initials: D
authors.lastname: Krause
authors.forename: M
authors.initials: M
authors.lastname: Schott
authors.forename: V
authors.initials: V
authors.lastname: Lamounier-Zepter
authors.forename: A W
authors.initials: AW
authors.lastname: Krug
authors.forename: M
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.forename: S R
authors.initials: SR
authors.lastname: Bornstein
authors.forename: W A
authors.initials: WA
authors.lastname: Scherbaum
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000302:Adrenal Cortex / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000450:Aldosterone / Q000378:metabolism*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology*; D015398:Signal Transduction; D051153:Wnt Proteins; D051176:beta Catenin / Q000502:physiology*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D051153:Wnt Proteins; D051176:beta Catenin; D000098682:Steroidogenic Acute Regulatory Protein; D000450:Aldosterone; D006854:Hydrocortisone