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

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 upregulated 30 min after acute exercise and were correlated mainly with ATP levels and secondarily with metabolites related to glycolysis and lipolysis in muscle. Conclusions Similar to mice, the FNDC5 gene is expressed in human muscle. Age and muscle mass are the primary predictors of circulating irisin, with young male athletes having several fold higher irisin levels than middle-aged obese women. Circulating irisin levels increase in response to acute exercise whereas muscle FNDC5 mRNA and circulating irisin levels decrease after surgically induced weight loss in paral...

Longitudinal variation of circulating irisin after an energy restriction‐induced weight loss and following weight regain in obese men and women

“…The current and previously published results (Huh et al, 2012;Liu et al 2013;Park et al, in press;Stengel et al, 2012) mutually reinforce the correlation of irisin with BMI and strongly suggest that plasma irisin levels reflect the net adipose tissue in humans. Moreover, it was described a positive correlation between FNDC5 muscle Non-regainers subjects with successful weight maintenance (n 5 38) and regainers, subjects with weight regain 4 months after ending the hypocaloric diet (n 5 39).…”

“…However, the most powerful demonstration of the association between adiposity and circulating irisin levels is the change observed in irisin levels in obese patients underwent a weight-reduction program based on a hypocaloric diet, paralleling previous reports that showed a diminution on irisin after surgically-induced weight loss in only fourteen women (Huh et al, 2012). In the period of energy restriction treatment, the body weight of all patients decreased along with a concomitant reduction in irisin levels.…”

“…The sample size of the current trial was base on the equation published by Mera et al (1998) to detect differences for irisin between obese and normal-weight patients as well as the changes after the diet-induced weight loss and taking into account published values of circulating irisin standard deviation (Huh et al, 2012;Stengel et al, 2012). It was calculated for an effect size 0.5, an a 5 0.05, and a power (1 2 b) of 80%.Thus, the sample size was established at a minimum of 26 volunteers per group to detect differences according to the adiposity levels and 66 obese subjects who finished the nutritional intervention.…”

“…In contrast, recent studies have revealed a positive correlation between irisin circulating levels and BMI in humans (Huh et al, 2012;Park et al, in press;Stengel et al, 2012). Thus, it was shown that circulating irisin levels were higher in obese patients compared with normal-weight or anorexic patients (Stengel et al, 2012).…”

Increased FNDC5 is associated with insulin resistance in high fat-fed mice

“…Congruently, weight loss induced by bariatric surgery or diet/exercise intervention has resulted in associated reductions in plasma irisin levels (Huh et al. 2012; Sharma et al. 2012; Crujeiras et al.…”