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 PGC1a 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.

Obese with higher FNDC5/Irisin levels have a better metabolic profile, lower lipopolysaccharide levels and type 2 diabetes risk

“…Our results also go against works that put in doubt the FNDC5/irisin beneficial effects (26). Thus, the present study corroborate clinically with early studies in animals and in vitro (1,2) that associated FNDC5/irisin stimulus with a metabolic improvement in humans.…”

Myokines in insulin resistance and type 2 diabetes

“…Our group has recently published an analysis of genomic DNA, mRNA and expressed sequence tags indicating that FNDC5, the gene encoding the precursor of irisin, is present in rodents and most primates [100]. However, in humans we observed a mutation that changes the conserved start codon ATG to ATA.…”

“…As summarised in Table 1, in vitro studies have shown that IL-6 increases myotube fatty acid oxidation and lipolysis via AMPK activation [32,33]. [46] No data available regarding endocrine metabolic effects of muscle-derived BDNF IL-6 ↑ GLUT4 translocation [19,20] ↑ Glucose uptake [15,19] ↑ Glycogen synthesis [18,20] ↑ Fatty acid oxidation [18][19][20] ↑ Lipolysis [32][33][34] Liver: ↑ Glucose production [23] Intestine: ↑ GLP-1 secretion of L cells [52] Pancreas: ↑ Beta cell proliferation [52] ↑ GLP-1 secretion of alpha cells [52] ↑ Proliferation and ↓ apoptosis of alpha cells [51] IL-13 ↑ Glucose uptake [28] ↑ Glucose oxidation [28] ↑ Glycogen synthesis [28] Liver: ↓ Glucose production [29] IL-15 ↑ Fatty acid oxidation [43] Adipose tissue: ↓ Lipid accumulation [44,45] ↑ Adiponectin secretion [44] Irisin No data available Adipose tissue: ↑ White to brown shift [98,111] No effect on browning [100] FGF21 ↑ Glucose uptake [99,136] Adipose tissue: ↑ White to brown shift [99] ↑ Glucose uptake [99] ↑ Adiponectin secretion [127,128] Liver: ↑ Fatty acid oxidation [137] ↑ Gluconeogenesis [137] Recently, a study using isolated mouse muscle reported that IL-6...…”

“…Western blot analysis indicated circulating irisin in both mice and humans and was increased after exercise. However, the antibody used in these analyses is not able to detect irisin since it binds to the non-secreted portion of FNDC5 [100,101]. Therefore, these data need to be reconsidered and re-assessed using independent experimental approaches.…”

Brown adipose tissue: what have we learned since its recent identification in human adults

“…The hormone was isolated in mice but the same group also detected circulating levels of this hormone in humans. A great debate is ongoing, after some previous findings questioned the relevance of the hormone (91,92). Raschke suggested that humans are unable to cleave FDNC5 and the detected irisin may just be laboratory interferences and even exogenous irisin administration in human cells does not appear to have the expected result.…”