title: Evidence against a beneficial effect of irisin in humans.
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.
authors.affiliation: Paul-Langerhans-Group, Integrative Physiology, German Diabetes Center, Düsseldorf, Germany.
authors.forename: Silja
authors.initials: S
authors.lastname: Raschke
authors.forename: Manuela
authors.initials: M
authors.lastname: Elsen
authors.forename: Hans
authors.initials: H
authors.lastname: Gassenhuber
authors.forename: Mark
authors.initials: M
authors.lastname: Sommerfeld
authors.forename: Uwe
authors.initials: U
authors.lastname: Schwahn
authors.forename: Barbara
authors.initials: B
authors.lastname: Brockmann
authors.forename: Raphael
authors.initials: R
authors.lastname: Jung
authors.forename: Ulrik
authors.initials: U
authors.lastname: Wisløff
authors.forename: Arnt E
authors.initials: AE
authors.lastname: Tjønna
authors.forename: Truls
authors.initials: T
authors.lastname: Raastad
authors.forename: Jostein
authors.initials: J
authors.lastname: Hallén
authors.forename: Frode
authors.initials: F
authors.lastname: Norheim
authors.forename: Christian A
authors.initials: CA
authors.lastname: Drevon
authors.forename: Tania
authors.initials: T
authors.lastname: Romacho
authors.forename: Kristin
authors.initials: K
authors.lastname: Eckardt
authors.forename: Juergen
authors.initials: J
authors.lastname: Eckel
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D018387:Codon, Initiator / Q000235:genetics*; D005260:Female; D005353:Fibronectins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D055815:Young Adult
chemical_list: D018387:Codon, Initiator; C577593:FNDC5 protein, human; D005353:Fibronectins; D049452:Green Fluorescent Proteins
references.citation: Nature. 2012 Aug 16;488(7411):286-7
references.pmid: 22895329
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1115-25
references.pmid: 21368268
references.citation: Cell Metab. 2007 Jul;6(1):38-54
references.pmid: 17618855
references.citation: Mol Cell Biol. 1989 Nov;9(11):5073-80
references.pmid: 2601709
references.citation: Cell. 1998 Mar 20;92(6):829-39
references.pmid: 9529258
references.citation: Physiol Rev. 2004 Jan;84(1):277-359
references.pmid: 14715917
references.citation: N Engl J Med. 2009 Apr 9;360(15):1500-8
references.pmid: 19357405
references.citation: N Engl J Med. 2009 Apr 9;360(15):1518-25
references.pmid: 19357407
references.citation: Diabetes. 2009 Jul;58(7):1526-31
references.pmid: 19401428
references.citation: Horm Res. 2002;57 Suppl 1:29-33
references.pmid: 11979019
references.citation: Nature. 2012 Jan 11;481(7382):463-8
references.pmid: 22237023
references.citation: J Physiol. 2003 Feb 1;546(Pt 3):851-8
references.pmid: 12563009
references.citation: Nat Med. 2013 May;19(5):631-4
references.pmid: 23603813
references.citation: Circ Heart Fail. 2012 Nov;5(6):812-8
references.pmid: 23001918
references.citation: FASEB J. 2009 Sep;23(9):3113-20
references.pmid: 19417078
references.citation: Cell Metab. 2006 Feb;3(2):111-22
references.pmid: 16459312
references.citation: Nat Med. 2013 May;19(5):635-9
references.pmid: 23603815
references.citation: Cell Metab. 2009 Feb;9(2):203-9
references.pmid: 19187776
references.citation: Cell Metab. 2013 May 7;17(5):798-805
references.pmid: 23663743
references.citation: Cell. 2012 Jul 20;150(2):366-76
references.pmid: 22796012
references.citation: Diabetologia. 2012 Apr;55(4):1128-39
references.pmid: 22282161
references.citation: Am J Physiol Cell Physiol. 2010 Apr;298(4):C807-16
references.pmid: 20089933
references.citation: Biochem J. 2006 Sep 1;398(2):153-68
references.pmid: 16898874
references.citation: J Strength Cond Res. 2007 Feb;21(1):157-63
references.pmid: 17313291
references.citation: Nature. 2008 Aug 21;454(7207):1000-4
references.pmid: 18719589
references.citation: Peptides. 2013 Jan;39:125-30
references.pmid: 23219488
references.citation: Proc Natl Acad Sci U S A. 1990 Nov;87(21):8301-5
references.pmid: 2236042
references.citation: Nutr Metab Cardiovasc Dis. 2013 Jun;23(6):582-90
references.pmid: 22633794
references.citation: Am J Physiol Endocrinol Metab. 2011 Nov;301(5):E1013-21
references.pmid: 21828336
references.citation: Cell. 2002 Dec 27;111(7):931-41
references.pmid: 12507421
references.citation: Nucleic Acids Res. 2011 May;39(10):4220-34
references.pmid: 21266472
references.citation: Metabolism. 2012 Dec;61(12):1725-38
references.pmid: 23018146
references.citation: Gene. 2002 Sep 4;297(1-2):79-83
references.pmid: 12384288
references.citation: J Clin Endocrinol Metab. 2013 Apr;98(4):E769-78
references.pmid: 23436919
references.citation: J Biol Chem. 2010 Mar 5;285(10):7153-64
references.pmid: 20028987
references.citation: BMC Bioinformatics. 2007 Aug 30;8:318
references.pmid: 17760957
references.citation: Pflugers Arch. 1997 Mar;433(5):664-8
references.pmid: 9049153
references.citation: Diabetes. 2009 Dec;58(12):2731-40
references.pmid: 19720798
references.citation: N Engl J Med. 2009 Apr 9;360(15):1509-17
references.pmid: 19357406
references.citation: J Clin Endocrinol Metab. 2009 Dec;94(12):4635-44
references.pmid: 19837918
references.citation: Arch Physiol Biochem. 2012 Feb;118(1):22-30
references.pmid: 22117101
references.citation: Neuroscience. 2013 Feb 12;231:296-304
references.pmid: 23219938
references.citation: Dev Dyn. 2002 Jun;224(2):154-67
references.pmid: 12112469
references.citation: Am J Clin Nutr. 2005 Jul;82(1 Suppl):215S-217S
references.pmid: 16002823
references.citation: Diabetes Res Clin Pract. 2013 Apr;100(1):96-101
references.pmid: 23369227
references.citation: Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):523-31
references.pmid: 19896888
references.citation: Nature. 2012 Aug 30;488(7413):E9-10; discussion E10-1
references.pmid: 22932392
references.citation: Nature. 2008 Aug 21;454(7207):961-7
references.pmid: 18719582
references.citation: Nutr Metab (Lond). 2012 Oct 15;9(1):90
references.pmid: 23067400