The current findings indicated the significantly higher circulating levelof irisinin NWO subjects compared to controls who had normal weight and normal BF%. However, previous trials reported the increased blood level of irisin in the obese subjects. In this context, Saleh et al.found significantly increased irisin level in obese andoverweight women compared to normal weight ones [16].
Similarly, the reports of Ivanov et al. [17], Stengel et al. [10], and Wen et al.[18] showed the positive association between irisin levels and BMI in healthy non-diabetic subjects. The results of Stengle et al. [10] and Huh et al. [7] studies indicated that circulating levels of irisin were higher in healthy subjects with morbid obesity than normal weight controls. On the other hand, Liu et al. reported that circulating irisin level had a negative association with BMI, waist to hip ratio and BF% in men [13]. However in this study, body composition was not measured directly.
It has been suggested that BF% is a better indicator oftotal adiposity compared to BMI. In support of this statement, our results showed that in NWO subject who had normal range of BMI and higher BF%, the serum level of irisin was significantly higher than controls.
Regarding to possible mechanism, it is suggested that increased circulating irisin in obesity is an adaptive compensatory response to obesity-induced disturbed metabolism such as decreased insulin level [16]. Alternatively,” irisin resistance” may be another description for increased levels of irisin in obesity, as has already established for leptin or insulin in obesity [11].
According to our observation in this study, serum irisin levelcorrelated positively with FBS and insulin levels in NWO subjects. This correlation was negative in controls, although it was only significant between irisin and insulin level in controls.
Gomer et al. reported positive correlation between irisin level and HbA1c in T2D patients with and without obesity [19]. Liu et al. showed the positive association between circulating irisin and FBS in non-obese, non-diabetic individuals [13]. In consistence to this results, Huh et al., Stengel et al. and Liu et al. showed positive correlation between serum levels of irisin and FBS [7, 10, 13]. Data from our study showed that the serum levels of FBS and insulin were higher significantly in NWO patients compared to controls. Another study speculated that long time exposure to high blood glucose, irrespective of BMI, was associated significantly with decreased serum level of irisin in diabetic patients [7, 13]. Contrary to type 2 diabetes and despite to higher level of FBS and insulin, NWO patients had higher levels of irisin. Patients with NWO are susceptible to development of T2D; therefore, it is possible that the irisin levels could be decreased in long-time in NWO subjects. In addition, the high serum level of irisin in NWO subjects might be compensatory response to condition called “irisin resistance”, similar to T2 DM.
In agreement with this result, our study showed that the adipose tissue might be the main source of irisin secretion in NWO subjects, because NWO subjects had a higher BF% than controls.
Previous studies found that the activity oftranscriptional co-activator PPAR-γ co-activator-1 α (PGC1α), a molecule up-stream of irisin, in skeletal muscles and therefore circulating irisin level was lower in patients with type 2 diabetes or pre-diabetes than healthy obese subjects [20–22].
On the other hand, in patients with abnormal blood glucose or T2DM, the expressions of FNDC5/irisin are decreased in adipose tissue and skeletal muscles.
Saleh et al. suggested that the glucose intolerance may gradually up regulate the skeletal muscles expression of FNDC5/irisin in non-diabetic subjects [23]. According to this statement and despite to the results of previous studies, we expect the high circulating irisin level in patients with T2DM who are exposed to high level of glucose. To illustrate this conflict observation, we mentioned the results of other studies suggested timelyregulation of local and circulating irisin with tissue-specific mechanisms in different physiological status such as obesity, pre-diabetes and T2DM [24, 25]. Also, Choi et al. and Huh et al. showed that decreased blood irisin level could expose subjects to the development of insulin resistance and T2DM [7, 14]. Similar to the results of Saleh et al., study, we found that serum irisin was significantly negatively associated with insulin level in control subjects [16].
Interestingly, it was shown the opposite expression of FNDC5 in skeletal muscle and adipose tissue of T2D patients compared to lean, obese and pre-diabetic subjects [26]. Diabetic patients displayed the lowest expression of FNDC5 in adipose tissue and circulating irisin level. The muscle expression of FNDC5 was similar in diabetic patients and obese subjects. It is suggested that glucose and lipid, not insulin might be inhibitory regulatory factor in muscle FNDC5 expression in metabolic disorders. It is plausible to think that different interaction exist between expressions of FNDC5 in skeletal muscle and adipose tissue in patients with NWO who had increased insulin and glucose levels. In addition, this expression might change during long term dependant to the glycemic control in NWO subjects.
Our current data also revealed a positive correlation between irisin and HDL-c, LDL-c, TG and a negative correlation association between irisin and TC in NWO subjects. In addition, our results indicate that circulating irisin correlated positively with HDL-c and TCand correlated negatively with LDL-c and TG in control group.
A limited study was performed to evaluate the association between irisin and lipid profile in various populations with obesity or diabetes and both of them. Liu et al. reported that serum level of irisin correlated positively with total cholesterol and TG in non- obese, non- diabetic subjects [13]. The significant association between irisin and HDL-c in healthy non-diabetic subjects in Benton et al. study, suggested a protective role for circulating irisin in cardiovascular disease [27], which is similar to our result in NWO and controls. Another study conducted by Sanchis-Gomer et al., reveals no significant relationship between irisin and TC, TG and LDL [28]. In contrary, Wen et al. study showed a significantpositive correlations of TC, TG and LDL with circulating irisin in non- diabetic participants [18]. The positive association between serum level of irisin and TG was shown in Liu et al. study [13]. Previous studies showed that muscle FNDC5 was positively associated with TG [7], and negatively associated with HDL-c [7, 12]. For the first time, Saleh et al. reported that serum irisin has a positive relationship with both leptin and insulin in type 2 diabetes [16]. It is plausible to think that the association between irisin and lipid profile may be mediated by its effect on leptin.
The correlation of irisin with TG, LDL-c and HDL-c was inversely between NWO and control subjects. More studies are needed to establish the detail association between irisin and lipid profiles in subjects with NWO compared to obese, diabetes and non- obese, non-diabetic healthy subjects. In addition to skeletal muscles and adipose tissue, FNDC5 mRNA/irisin detected in various tissues, including pericardium, kidney, liver, lung and neurons in human [7, 9, 29–31]. It was suggested thatthe muscle/adipose irisin secretion ratio might vary dependent to the physiological status. In athletes with trained muscles by exercise, muscle tissue would actively increase FNDC5/irisin but, in obesity, the adipose tissue is the main source of FNDC5/ irisin secretion [32].
The limitations of our study are its small sample size and lack of information about the FNDC5 expression and irisin level in adipose tissue, skeletal muscles and its ratio in subjects with normal weight obesity. There was no data about the life quality and socioeconomic factors in our study that considered as a limitation of our study. The strength of our study is that this is the first study that investigated blood irisin level and its association with biochemical parameters in subjects with normal weight obesity.