Evidence against a beneficial effect of irisin in humans

PLoS One. 2013 Sep 11;8(9):e73680. doi: 10.1371/journal.pone.0073680. eCollection 2013.

Abstract

Brown adipose tissue has gained interest as a potential target to treat obesity and metabolic diseases. Irisin is a newly identified hormone secreted from skeletal muscle enhancing browning of white fat cells, which improves systemic metabolism by increasing energy expenditure in mice. The discovery of irisin raised expectations of its therapeutic potential to treat metabolic diseases. However, the effect of irisin in humans is unclear. Analyses of genomic DNA, mRNA and expressed sequence tags revealed that FNDC5, the gene encoding the precursor of irisin, is present in rodents and most primates, but shows in humans a mutation in the conserved start codon ATG to ATA. HEK293 cells transfected with a human FNDC5 construct with ATA as start codon resulted in only 1% full-length protein compared to human FNDC5 with ATG. Additionally, in vitro contraction of primary human myotubes by electrical pulse stimulation induced a significant increase in PGC1α mRNA expression. However, FNDC5 mRNA level was not altered. FNDC5 mRNA expression in muscle biopsies from two different human exercise studies was not changed by endurance or strength training. Preadipocytes isolated from human subcutaneous adipose tissue exhibited differentiation to brite human adipocytes when incubated with bone morphogenetic protein (BMP) 7, but neither recombinant FNDC5 nor irisin were effective. In conclusion, our findings suggest that it is rather unlikely that the beneficial effect of irisin observed in mice can be translated to humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipocytes / metabolism
  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Codon, Initiator / genetics*
  • Female
  • Fibronectins / genetics*
  • Fibronectins / metabolism
  • Gene Expression Profiling*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Microscopy, Fluorescence
  • Middle Aged
  • Molecular Sequence Data
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Mutation*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Sequence Homology, Nucleic Acid
  • Young Adult

Substances

  • Codon, Initiator
  • FNDC5 protein, human
  • Fibronectins
  • Green Fluorescent Proteins

Grants and funding

This work was supported by the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen (Ministry of Science and Research of the State of North Rhine-Westphalia), the Bundesministerium für Gesundheit (Federal Ministry of Health), and the Deutsche Forschungsgemeinschaft (EC 440/1-1). T. Romacho is the recipient of a fellowship from Caja Madrid Foundation. This study was supported in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). Additionally, this study was funded by K.G. Jebsen Foundation, The Norwegian Council on Cardiovascular Disease, University of Oslo, The Johan Throne Holst Foundation, Freia Medical Foundation, and Anders Jahres Medical Research Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.