title: Semaphorin 3C is a novel adipokine linked to extracellular matrix composition.
abstract: OBJECTIVE
  Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function.
  
  
  METHODS
  Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes.
  
  
  RESULTS
  We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMAIR], and the rate constant for the insulin tolerance test [KITT]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of β-oxidation genes. This could in part be explained by the significant downregulation of its cognate receptors during adipogenesis. In contrast, in pre-adipocytes, SEMA3C increased the production/secretion of several ECM components (fibronectin, elastin and collagen I) and matricellular factors (connective tissue growth factor, IL6 and transforming growth factor-β1). Furthermore, the expression of SEMA3C in human WAT correlated positively with the degree of fibrosis in WAT.
  
  
  CONCLUSIONS
  SEMA3C is a novel adipokine regulated by weight changes. The correlation with WAT hypertrophy and fibrosis in vivo, as well as its effects on ECM production in human pre-adipocytes in vitro, together suggest that SEMA3C constitutes an adipocyte-derived paracrine signal that influences ECM composition and may play a pathophysiological role in human WAT.
authors.affiliation: Department of Medicine, Lipid Laboratory, Karolinska Institutet, Stockholm, Sweden. niklas.mejhert@ki.se
authors.forename: N
authors.initials: N
authors.lastname: Mejhert
authors.forename: F
authors.initials: F
authors.lastname: Wilfling
authors.forename: D
authors.initials: D
authors.lastname: Esteve
authors.forename: J
authors.initials: J
authors.lastname: Galitzky
authors.forename: V
authors.initials: V
authors.lastname: Pellegrinelli
authors.forename: C-I
authors.initials: CI
authors.lastname: Kolditz
authors.forename: N
authors.initials: N
authors.lastname: Viguerie
authors.forename: J
authors.initials: J
authors.lastname: Tordjman
authors.forename: E
authors.initials: E
authors.lastname: Näslund
authors.forename: P
authors.initials: P
authors.lastname: Trayhurn
authors.forename: D
authors.initials: D
authors.lastname: Lacasa
authors.forename: I
authors.initials: I
authors.lastname: Dahlman
authors.forename: V
authors.initials: V
authors.lastname: Stich
authors.forename: P
authors.initials: P
authors.lastname: Lång
authors.forename: D
authors.initials: D
authors.lastname: Langin
authors.forename: A
authors.initials: A
authors.lastname: Bouloumié
authors.forename: K
authors.initials: K
authors.lastname: Clément
authors.forename: M
authors.initials: M
authors.lastname: Rydén
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*
chemical_list: D054392:Adipokines; C543908:Sema3C protein, human; D039961:Semaphorins