Evidence against a Beneficial Effect of Irisin in Humans

Silja Raschke,Christian A Drevon,Manuela Elsen,Mark Sommerfeld,Raphael Jung,Truls Raastad,Juergen Eckel,Jostein Hallén,Uwe Schwahn,Barbara Brockmann,Arnt E Tjønna,Ulrik Wisløff,Kristin Eckardt,Tania Romacho,Hans Gassenhuber,Frode Norheim

doi:10.1371/journal.pone.0073680

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.

Highlights

Obesity and the involved risk of developing metabolic diseases represent a major global public health challenge
Start Codon of FNDC5 Gene is Mutated in Humans A multi-species sequence alignment of the FNDC5 exon 1 demonstrated that FNDC5 genes from different species like rat, mouse, gibbon, gorilla and chimp display a conserved ATG translation start site, except for the human sequence (Figure 1A)
Kozak et al showed that a mutated start codon to ATA, even in a perfect context (GCCXCCATAG, X = A or G, Figure 1A), was highly unlikely to serve as a translation site and resulted in low translation efficiency [26]

Summary

Introduction

Obesity and the involved risk of developing metabolic diseases represent a major global public health challenge. Brown adipose tissue (AT) has drawn attention as a novel preventive and therapeutic target to treat obesity and metabolic diseases like type 2 diabetes. Whereas white AT is the primary site of triglyceride storage, brown AT is specialized in energy expenditure. In order to maintain body temperature in a cold environment, brown AT oxidizes fatty acids and generates heat [5] by the mitochondrial uncoupling protein 1 (UCP1). UCP1 knock-out mice are cold sensitive and tend to develop obesity, even when fed a control diet [6], whereas experimental approaches aiming to increase the amount and activity of brown AT reduce the development of obesity [7]. Brown AT has been detected in humans and is found in anatomically discrete depots, with the most common location in adults in the cervical-supraclavicular depot [8,9,10,11,12]

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