title: METRNL decreases during adipogenesis and inhibits adipocyte differentiation leading to adipocyte hypertrophy in humans.
abstract: Meteorin-like (METRNL) is a recently described circulating protein shown to be highly expressed in white adipose tissue and to beneficially affect energy metabolism in mice.
  
  
  
  We systematically evaluated the role of METRNL for human adipogenesis and its association with obesity, browning and hyperinsulinemia in children. In addition, we assessed the functional relevance of METRNL for human adipogenesis.
  
  
  
  METRNL expression decreased during human adipocyte differentiation in vitro. Coherently, METRNL expression was lower in isolated adipocytes compared with stromal vascular fraction (SVF) cells in human samples. Withdrawal of the peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone from adipogenic media partially preserved the METRNL downregulation during adipogenesis. METRNL expression was higher in adipocytes of obese compared with lean children and correlated with adipocyte size, whereas in SVF METRNL expression correlated with proliferation capacity. Concordantly, overexpression of METRNL inhibited human adipocyte differentiation as shown by decreased lipogenesis and lower expression of PPARγ and markers of adipogenesis, whereas experimental downregulation promoted adipogenesis. Proliferation, in contrast, was advanced by METRNL overexpression. These interactions with adipose tissue dynamics may contribute to the clinically observed body mass index-independent association of METRNL expression with hyperinsulinemia and adipose tissue inflammation in human samples. METRNL was not associated with UCP1 expression or induction of browning in white adipocytes.
  
  
  
  Taken together, the downregulation of METRNL during adipogenesis and functional induction of increased proliferation in SVF cells with concomitant inhibition of adipocyte differentiation may result in hypertrophic AT accumulation. This may also explain our observations of increased METRNL expression in adipocytes but not SVF cells in obese children compared with lean children and the subsequent hyperinsulinemia.
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.|Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Löffler
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.|Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Landgraf
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Rockstroh
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Schwartze
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.|Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Dunzendorfer
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kiess
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig (CPL), Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany.|Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Körner
mesh_terms: D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology*; D050156:Adipogenesis; D054392:Adipokines / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000473:pathology*; D002648:Child; D005260:Female; D006801:Humans; D006984:Hypertrophy; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009765:Obesity / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D054392:Adipokines; D036341:Intercellular Signaling Peptides and Proteins; C000593412:Metrnl protein, human; D047495:PPAR gamma