title: Adiporedoxin, an upstream regulator of ER oxidative folding and protein secretion in adipocytes.
abstract: OBJECTIVE
  Adipocytes are robust protein secretors, most notably of adipokines, hormone-like polypeptides, which act in an endocrine and paracrine fashion to affect numerous physiological processes such as energy balance and insulin sensitivity. To understand how such proteins are assembled for secretion we describe the function of a novel endoplasmic reticulum oxidoreductase, adiporedoxin (Adrx).
  
  
  METHODS
  Adrx knockdown and overexpressing 3T3-L1 murine adipocyte cell lines and a knockout mouse model were used to assess the influence of Adrx on secreted proteins as well as the redox state of ER resident chaperones. The metabolic phenotypes of Adrx null mice were characterized and compared to WT mice. The correlation of Adrx levels BMI, adiponectin levels, and other inflammatory markers from adipose tissue of human subjects was also studied.
  
  
  RESULTS
  Adiporedoxin functions via a CXXC active site, and is upstream of protein disulfide isomerase whose direct function is disulfide bond formation, and ultimately protein secretion. Over and under expression of Adrx in vitro enhances and reduces, respectively, the secretion of the disulfide-bonded proteins including adiponectin and collagen isoforms. On a chow diet, Adrx null mice have normal body weights, and glucose tolerance, are moderately hyperinsulinemic, have reduced levels of circulating adiponectin and are virtually free of adipocyte fibrosis resulting in a complex phenotype tending towards insulin resistance. Adrx protein levels in human adipose tissue correlate positively with adiponectin levels and negatively with the inflammatory marker phospho-Jun kinase.
  
  
  CONCLUSIONS
  These data support the notion that Adrx plays a critical role in adipocyte biology and in the regulation of mouse and human metabolism via its modulation of adipocyte protein secretion.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA ; Department of Cell Biology, Harvard University School of Medicine, 240 Longwood Avenue Boston, MA 02115, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Libin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Collette J
authors.initials: CJ
authors.lastname: Laflamme
authors.affiliation: Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Kalypso
authors.initials: K
authors.lastname: Karastergiou
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Tova
authors.initials: T
authors.lastname: Meshulam
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Ding
authors.affiliation: Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Cell Biology, Harvard University School of Medicine, 240 Longwood Avenue Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fried
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA ; Department of Medicine, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Pilch
keywords: Adipocyte; Adipokine; Disulfide bond formation; Endoplasmic reticulum; Oxidoreductase; Protein secretion