Journal Article

Common Genetic Variation in the Human FNDC5 Locus, Encoding the Novel Muscle-Derived ‘Browning’ Factor Irisin, Determines Insulin Sensitivity

de Angelis, Martin Hrabě, Weigert, Cora, Machicao, Fausto, Stefan, Norbert, Krook, Anna, Häring, Hans-Ulrich, Schick, Fritz, Berti, Lucia, Scheler, Mika, Böhm, Anja, Fritsche, Andreas, Staiger, Harald, Machann, Jürgen

2013

Overview

Recently, the novel myokine irisin was described to drive adipose tissue 'browning', to increase energy expenditure, and to improve obesity and insulin resistance in high fat-fed mice. Here, we assessed whether common single nucleotide polymorphisms (SNPs) in the FNDC5 locus, encoding the irisin precursor, contribute to human prediabetic phenotypes (overweight, glucose intolerance, insulin resistance, impaired insulin release). A population of 1,976 individuals was characterized by oral glucose tolerance tests and genotyped for FNDC5 tagging SNPs. Subgroups underwent hyperinsulinaemic-euglycaemic clamps, magnetic resonance imaging/spectroscopy, and intravenous glucose tolerance tests. From 37 young and 14 elderly participants recruited in two different centres, muscle biopsies were obtained for the preparation of human myotube cultures. After appropriate adjustment and Bonferroni correction for the number of tested variants, SNPs rs16835198 and rs726344 were associated with in vivo measures of insulin sensitivity. Via interrogation of publicly available data from the Meta-Analyses of Glucose and Insulin-related traits Consortium, rs726344's effect on insulin sensitivity was replicated. Moreover, novel data from human myotubes revealed a negative association between FNDC5 expression and appropriately adjusted in vivo measures of insulin sensitivity in young donors. This finding was replicated in myotubes from elderly men. This study provides evidence that the FNDC5 gene, encoding the novel myokine irisin, determines insulin sensitivity in humans. Our gene expression data point to an unexpected insulin-desensitizing effect of irisin.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipocytes / Adipose tissue / Adult / Biology / Blood Glucose - metabolism / Body Fat Distribution / Body weight / Browning / Clamps / Consortia / Data processing / Desensitization / Diabetes / Diabetes Mellitus, Type 2 - genetics / Endocrinology / Energy expenditure / Environmental health / Ethics / Female / Fibronectins - genetics / Fibronectins - metabolism / Gene expression / Gene Expression Regulation / Gene Frequency / Gene loci / Genes / Genetic aspects / Genetic diversity / Genetic Loci - genetics / Genetic Predisposition to Disease - genetics / Genetics / Geriatrics / Glucose / Glucose Intolerance - genetics / Glucose Intolerance - metabolism / Glucose tolerance / Hormones / Humans / In vivo methods and tests / Insulin / Insulin - metabolism / Insulin resistance / Insulin Resistance - genetics / Insulin Secretion / Internal medicine / Interrogation / Intolerance / Intravenous administration / Lipids / Magnetic resonance / Magnetic resonance imaging / Male / Medicine / Meta-analysis / Metabolic disorders / Middle Aged / Muscle Fibers, Skeletal - metabolism / Muscles / Musculoskeletal system / Myotubes / Nephrology / Obesity / Older people / Overweight / Overweight - genetics / Overweight - metabolism / Phenotype / Polymorphism, Single Nucleotide / Prediabetic state / Prediabetic State - genetics / Prediabetic State - metabolism / Preventive medicine / Proteins / Reproducibility of Results / Rodents / Sensitivity / Sensitivity analysis / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Spectroscopy / Subgroups / Thermogenesis / Type 2 diabetes