In addition, we examined whether in vitro FNDC5 gene expression in human myotubes reflects prediabetes-related metabolic in vivo traits of the donors.Īn overall study group of 1,976 White European individuals from Southern Germany was recruited from the ongoing Tübingen Family study for type 2 diabetes (TÜF) that currently encompasses more than 2,300 participants at increased risk for type 2 diabetes (i.e., non-diabetic individuals with family history of type 2 diabetes and/or diagnosis of impaired fasting glycaemia. Therefore, we assessed in 1,976 German individuals at increased risk for type 2 diabetes whether common single nucleotide polymorphisms (SNPs with minor allele frequencies ≥0.05) in the human FNDC5 locus contribute to the prediabetic phenotypes overweight, glucose intolerance, insulin resistance, or impaired insulin release.
Whether irisin or the FNDC5 gene, encoding its membrane-resident protein precursor (MIM ID *611906), is involved in human metabolic disease is currently unknown. Finally, adenoviral Fndc5 overexpression in mice increased energy expenditure (probably via enhanced thermogenesis) and improved obesity and insulin resistance induced by high-fat feeding. This finding is in keeping with the observation of subcutaneous white adipose tissue ‘browning’ in PGC-1α-transgenic mice due to an increase in brown adipocyte number.
Irisin treatment of differentiating primary murine preadipocytes induced, in a PPAR-α-dependent manner, the expression of brown fat genes (including Ucp1), pointing to trans-determination and/or trans-differentiation of white adipose precursor cells.
After FNDC5 cleavage by a still unknown protease, irisin is released from muscle cells, enters the circulation, and is detectable in murine and human plasma.
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Expression of its gene was shown to be driven by muscle-specific transgenic overexpression of the exercise-responsive transcriptional co-activator peroxisome proliferator-activated receptor (PPAR)-γ co-activator-1α (PGC-1α) and, more physiologically, by three weeks of free wheel running in mice and by ten weeks of supervised endurance exercise training in humans. Irisin is released upon cleavage of the plasma membrane protein fibronectin type III domain-containing protein 5 (FNDC5). Pathophysiological roles of individual myokines, such as interleukin-6, and hepatokines, such as sex hormone-binding globulin and fetuin-A –, in the development of human metabolic diseases are currently emerging.Ī novel intriguing myokine, termed irisin, was very recently described by Boström et al. More recently, it was recognized that skeletal muscle and liver are also able to secrete, e.g., upon metabolic or physical stress, substantial amounts of metabolically active hormones, in analogy termed myokines and hepatokines, respectively –. The importance of adipose tissue-derived hormones, collectively termed adipokines, for the regulation of glucose, lipid, and energy metabolism was convincingly shown, and it appears by now very plausible that dysregulated adipokine secretion significantly contributes to the pathogenesis of human metabolic diseases (i.e., obesity, atherosclerosis, type 2 diabetes). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. Norbert Stefan is supported by a Heisenberg professorship from the Deutsche Forschungsgemeinschaft (STE 1096/3-1), Anna Krook by the Swedish Research Council. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: The study was supported in part by a grant (01GI0925) from the German Federal Ministry of Education and Research (BMBF) to the German Centre for Diabetes Research (DZD e.V.). Received: NovemAccepted: MaPublished: April 25, 2013Ĭopyright: © 2013 Staiger et al. PLoS ONE 8(4):Įditor: Yong-Gang Yao, Kunming Institute of Zoology, Chinese Academy of Sciences, China (2013) Common Genetic Variation in the Human FNDC5 Locus, Encoding the Novel Muscle-Derived ‘Browning’ Factor Irisin, Determines Insulin Sensitivity. Citation: Staiger H, Böhm A, Scheler M, Berti L, Machann J, Schick F, et al.