FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise

• Published in: Metabolism, clinical and experimental clinical and experimental, 2012-12, Vol.61 (12), p.1725-1738
• Main Authors: Huh, Joo Young, Panagiotou, Grigorios, Mougios, Vassilis, Brinkoetter, Mary, Vamvini, Maria T, Schneider, Benjamin E, Mantzoros, Christos S
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - blood; Adiponectin; Adult; Age; Athletes; ATP; Bariatric Surgery; Biological and medical sciences; Biomarkers - blood; Body mass; Body Mass Index; Cholesterol; Cross-Sectional Studies; Endocrinology & Metabolism; Exercise; Feeding. Feeding behavior; Female; Fibronectins - blood; Fibronectins - genetics; Fibronectins - metabolism; FNDC5; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; ghrelin; Glucose; Glycolysis; Hormones; Hormones - blood; Humans; Insulin; Insulin-like growth factor I; Irisin; Lipolysis; Male; Membrane proteins; Metabolism; Metabolites; Middle Aged; mRNA; Muscles; Obesity; Obesity, Morbid - blood; Obesity, Morbid - surgery; Physical training; Regression analysis; RNA, Messenger - blood; Running; Surgery; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Weight Loss
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2012.09.002

Abstract Objective In mouse, PGC1-α overexpression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin. One prior study has shown that FNDC5 induces browning of subcutaneous fat in mice and mediates beneficial effects of exercise on metabolism, but a more recent study using gene expression arrays failed to detect a robust increase in FNDC5 mRNA in human muscles from exercising subjects. No prior study has reported on the physiological regulation and role of circulating irisin and FNDC5 in humans. Materials/Methods A. FNDC5 gene expression studies: We first examined tissue distribution of FNDC5 in humans. B. Cross-sectional studies: Predictors of FNDC5 mRNA expression levels were examined in muscle tissues from 18 healthy subjects with a wide range of BMI. Assays were optimized to measure circulating FNDC5 and irisin levels, and their associations with anthropometric and metabolic parameters were analyzed in two cross-sectional studies that examined 117 middle-aged healthy women and 14 obese subjects, respectively. C. Interventional studies: The effect of weight loss on FNDC5 mRNA and/or circulating irisin levels was examined in 14 obese subjects before and after bariatric surgery. The effect of acute and chronic exercise was then assessed in 15 young healthy adults who performed intermittent sprint running sessions over an 8 week period. Results Tissue arrays demonstrated that in humans, the FNDC5 gene is predominantly expressed in muscle. Circulating irisin was detected in the serum or plasma of all subjects studied, whereas circulating FNDC5 was detected in only a distinct minority of the subjects. Cross-sectional studies revealed that circulating irisin levels were positively correlated with biceps circumference (used as a surrogate marker of muscle mass herein), BMI, glucose, ghrelin, and IGF-1. In contrast, irisin levels were negatively correlated with age, insulin, cholesterol, and adiponectin levels, indicating a possible compensatory role of irisin in metabolic regulation. Multivariate regression analysis revealed that biceps circumference was the strongest predictor of circulating irisin levels underlying the association between irisin and metabolic factors in humans at baseline. Both muscle FNDC5 mRNA levels and circulating irisin levels were significantly downregulated 6 months after bariatric surgery. Circulating irisin levels were significantly upregulat