In the present study, we found that serum irisin levels were significantly lower in overweight subjects compared to controls in middle aged Chinese. Circulating irisin concentration was negatively correlated with adverse metabolic parameters including WC, WHR, fasting insulin, HOMA-IR and serum creatinine. Moreover, multiple linear regression revealed that irisin was significant in an inverse relationship with HOMA-IR. In addition, logistic regression showed that higher irisin was associated with decreased odds of overweight.
In accordance with our finding, Liu et al. also reported decreased irisin level in obese Han Chinese. Several studies have implicated the role of PGC-1α in pathogenesis of obesity and T2DM [17, 18]. Moreover, PGC-1α expression and its activity were significantly down-regulated in skeletal muscles in patients with obesity and T2DM [18, 19]. Irisin was discovered as a PGC-1α activated messenger of myocytes that linked physical inactivity, obesity and diabetes . Thus, it is possible that lower levels of irisin in overweight observed in our study might be caused by impaired PGC-1α expression and functions in their muscle tissues.
In study conducted in patients with insulin resistance, irisin levels were determined to increase with the insulin resistance and decrease as insulin sensitivity increases . On the contrary, we found a significant negative correlation of irisin with fasting insulin and HOMA-IR, positive correlation with insulin sensitivity index QUICKI. In agreement with our findings, Yan and coworkers showed that irisin was negatively associated with fasting insulin in a large Chinese population with MS . Another study by Shi et al. showed that elevated circulating irisin was associated with lower risk of insulin resistance indirectly through lowering fasting insulin in obesity. Shanaki M et al. also found that irisin was negatively correlated with HOMA-IR and insulin in patients with nonalcoholic fatty liver disease (NAFLD). A recent study showed a negative correlation of HOMA-IR with circulating irisin levels in young girls suggesting that irisin secretion at an early age might delay the onset of obesity, insulin resistance and T2DM. In our study, the negative correlation of irisin with markers of insulin resistance indicated that decreased irisin expression in response to decreasing insulin sensitivity and disturbance in metabolisms associated with obesity.
On the contrary, a study revealed that irisin was positively associated with markers of insulin resistance including HOMA-IR . Serum levels of irisin were positively associated with blood glucose levels and fasting insulin in healthy individuals, and in those with obesity but not T2DM in children and in women with polycystic ovary syndrome [8, 10, 24]. A meta-analysis revealed that irisin concentration was positively associated with insulin resistance in adults who do not have T2DM . The negative association between irisin and HOMA-IR observed in our study could be secondary results of impaired PGC-1α function in obesity. As we know, PGC-1α can stimulate the expression of irisin, which is induced by exercise and exerts profound activity in the WAT, stimulating browning of WAT and UCP1 expression. Importantly, this causes a significant increase in total body energy expenditure and resistance to obesity-linked insulin resistance .
Different types of diabetes may have different levels of irisin. The levels of irisin in type 1 diabetes are not fully defined yet, one study showed the level of irisin in patients with type 1 diabetes was higher than control, while another study showed opposite results. Most studies have shown that irisin levels were lower in patients with T2DM [28, 29]. A meta-analysis of 1289 patients with T2DM and 834 controls showed lower irisin in patients with T2DM . It is possible to conclude that irisin hormone is not only associated with exercise but also with hormones, insulin resistance, inflammation and autoimmunity.
Current study on irisin concentrations and adiposity parameters remains controversial [7-10, 30]. In accordance with our findings, some studies found a significant negative correlation of circulating irisin with WC  and WHR  in nondiabetic individuals. However, contradictory to our results most studies have revealed a positive correlation of serum irisin levels with BMI [7, 9, 28] and WC  in nondiabetic individuals. Van Marken Lichtenbelt et al showed that the amount of BAT was significantly decreased in association with obesity, with a negative linear relationship between BAT, BMI and percent body fat. Although we found there was no association between irisin and BMI; Pearson correlation showed that irisin was inversely associated with WC and WHR; suggesting abdominal obesity could be a link between decreased irisin and insulin resistance.
A population-based cohort included 967 non-diabetic people living in Germany , this study investigated the association between irisin and lipid levels, finding a significant association with favorable lipid profile; in particular, an inverse association of irisin with total cholesterol concentration. Buscemi S, et al also found a positive association between HDL-cholesterol concentrations and irisin concentration . However, we found a positive association between irisin and triglycerides, no association with total cholesterol or HDL-C.
We also found that irisin was negatively correlated with serum creatinine. Accordingly, Ates I et al. showed irisin was negatively associated with serum creatinine among patients with type 1 diabetes . A previous study conducted in patients with chronic renal failure, irisin levels were determined to be negatively correlated with creatinine, which is considered to result from the inhibition of FNDC5 by indoxyl sulphate which is a uremic toxin. The negative association between irisin and creatine suggest that creatinine may have a role in the pathophysiology of irisin or vice versa. Further studies are needed to uncover the possible underlying mechanism for this.
We do have some limitations in this study. Firstly, the cross-sectional study design was unable to provide information on prospective changes in each metabolic parameter and their association with irisin. Secondly, our sample size was relatively small, therefore we did not further sub-divide overweight patients by obesity level. So the conclusion should only be generalized to overweight rather than different grade of obesity. Moreover, there has been controversies regarding available irisin ELISA kits, including antibody specificity of antibody, its cross-reactivity with FNDC5 and the wide range of irisin levels between different studies . In addition, different ethnicity and lifestyle may have different results; generalization beyond Asian populations should be interpreted with caution.