Higher Baseline Serum Irisin Decreases Risk for Body Mass Index Increment in Chinese Populations: A 3.2-Year Cohort Study

Obesity has become one of the most common non-communicable chronic diseases worldwide, with excessive intake of high-calorie food and decreased physical activity being the primary driving factors [1]. Obese individuals are at increased risk of developing type 2 diabetes mellitus (T2DM), hyperlipidemia, hyperuricemia, respiratory obstruction, gastroesophageal reflux disease and cardiovascular diseases, all of which reduce life quality and aggravate the social burden of the individual. In recent years, skeletal muscle has been recognized as an endocrine organ that secretes hormones with beneficial effects on glucose, lipid and energy metabolism, an action which could explain the effective intervention of physical activities on reversing obesity [2]. Irisin, a newly discovered myokine, is proteolytically cleaved from fibronectin type III domain-containing protein 5 (FNDC5) and released into the blood [3]. Irisin is a signaling molecule which transmits messages between skeletal muscle and other endocrine organs. It has been proposed that irisin induces the expression of the uncoupling protein 1 (UCP1) gene and white adipose tissue browning and increases whole body energy expenditures [3]. In one study, the administration of r-irisin to obese mice fed a high-fat diet improved glucose tolerance and reduced bodyweight [4]. In another study, mCaROCK1 mice had low plasma irisin levels, characterized by obesity and insulin resistance, which were improved after irisin administration [5]. Thus, irisin has been receiving significant interest recently as it has the potential to become a new treatment target for obesity, as well as other metabolic disorders.

However, the results of studies conducted to date that have evaluated the correlation between circulating irisin levels and obesity in humans are controversial. Huh et al. demonstrated that circulating irisin was positively correlated with the body mass index (BMI) and fat-free mass in white healthy adult women and that the irisin concentration decreased with the loss of fat-free mass and decrease in BMI after bariatric surgery in morbidly obese subjects [6]. However, the decrease in circulating irisin disappeared after adjustment with fat-free mass [6]. In another study, Moreno et al. reported that circulating irisin was positively correlated with the BMI, body weight and insulin resistance in Caucasian sedentary subjects without diabetes [7], but in an earlier study Moreno-Navarrete et al. reported that obese Caucasians were characterized by lower FNDC5 gene expression in skeletal muscle and adipose tissue, as well as decreased serum irisin level [8]. Among Chinese adults with abdominal obesity, serum irisin has been found to have no correlation to BMI, body fat and muscle mass [9]. The discrepancies among the results of these clinical studies may be due to differences in the study populations (i.e. ethnicity; different metabolic characteristics) and the relatively small sample sizes. Moreover, most of them were cross-sectional studies that failed to determine whether circulating irisin is related to the development of obesity and other metabolic diseases.

Here we report the results of a 3.2-year longitudinal follow-up study. The aim of this study was to investigate the association between serum irisin and baseline obesity among subjects with different BMI values and to examine whether serum irisin level could be used as a marker to predict the risk of BMI increment.

Subjects were divided into three groups according to the tertiles of baseline serum irisin. Subjects with higher serum irisin levels had a significantly lower change in BMI and BF% and a higher baseline HDL-C (p < 0.05 in Table 1). Table 2 shows the association between serum irisin and clinical characteristics. Serum irisin was positively correlated to an active lifestyle with physical activity (β = 1.138, p  = 0.032) and negatively correlated to FPG level (β = − 0.996, p = 0.023), changes in BMI (β = − 0.533, p  = 0.002), WC (β = − 0.102, p  = 0.018), BF% (β = − 0.457, p  = 0.001) and CVAI (β = − 0.280, p  = 0.028). No significant correlation was observed between serum irisin and baseline BMI. The OR for BMI increment is shown in Table 3. In the crude analysis, factors associated with BMI increment over the 3.2-year study period were age (OR 1.735, 95% confidence interval [CI] 1.144–1.993, p  = 0.017), baseline serum irisin level (OR 0.952, 95% CI 903–0.993, p  = 0.021), baseline BMI (OR 0.954, 95% CI 0.913–0.997, p  = 0.034), baseline BF% (OR 0.971, 95% CI 0.944–0.998, p  = 0.038), baseline LDL-C (OR 2.122, 95% CI 1.212–3.176, p  = 0.008), baseline SBP (OR 0.986, 95% CI 0.974–0.998, p  = 0.024), baseline DBP (OR 0.981, 95% CI 0.962–0.990, p  = 0.042), change in WC (OR 1.103, 95% CI 1.099–1.553, p  = 0.010), change in weight (OR 1.145, 95% CI 1.094–4.864, p  = 0.010), change in BF% (OR 1.349, 95% CI 1.226–1.845, p  = 0.002), change in CVAI (OR 1.045, 95% CI 1.036–1.064, p  = 0.032) and change in HDL-C (OR 0.868, 95% CI 0.391–0.998, p  = 0.013). After adjustment with various factors (including age and baseline characteristics [BMI, BF%, LDL-C, SBP, DBP]), change in the obesity index (weight, WC, BF% and CVAI) and change in HDL-C), baseline serum irisin level and BMI were independent factors contributing to the decrease of BMI increment (baseline serum irisin: OR 0.747, 95% CI 0.652–0.949, p  = 0.002; baseline BMI: OR 0.683, 95% CI 0.378–0.854, p  = 0.012), but larger change in BF% was an independent risk factor associated with BMI increment (OR 1.367, 95% CI:1.233–1.513, p  = 0.022).

The aim of our study was to explore the association between serum irisin and obesity. We found that the baseline serum irisin level was not associated with baseline BMI, WC, BF% and CVAI. To our knowledge, no study has yet examined the association between irisin and change in obesity index without intervention. Therefore, we explored the possible predictive value of baseline serum irisin for change in obesity index in populations with a well-distributed spectrum of BMI values and found that higher serum irisin level at baseline independently predicted a decrease in the BMI over 3.2 years.

To date, results from different studies assessing the association between obesity and irisin are contradictory [6, 7, 15‐18]. Choi and colleagues reported that serum irisin level was inversely correlated with BMI in a Korean population consisting of over 20-year-olds [15]. Klangjareonchai et al. found that the serum irisin was negatively associated with the BMI in healthy Thai men [16]. Among Caucasian populations, results from cross-sectional studies indicate a positive association between serum irisin level and parameters of adiposity, such as BMI, weight and fat mass [6, 7, 17, 18], which can be explained by the significant reduction in inrisin concentration with a decease in weight and BMI [6, 17]. The participants in these different studies were in different metabolic states and of different ethnicity, possibly contributing to the inconsistent results. Only a few studies conducted to date enrolled subjects with different BMIs, and the subgroup sample size based on different BMIs were < 50, which is relatively small [19, 20]. Compared with these previous studies, our study had a sample size of nearly 100 subjects per subgroup, and each subject was matched by sex and age. However, we failed to find that circulating irisin was associated with the baseline BMI, weight and BF%; these results are consistent with those from a number of other Chinese clinical studies [9, 21]. Taking into account past results together with our results, no consistent association has been found between serum irisin level and the baseline obesity index. Larger cross-sectional and prospective studies in different populations are needed for further investigation.

Interestingly, we found that baseline serum irisin level was negatively associated with changes in BMI, WC, BF% and CVAI and that a higher baseline serum irisin level was associated with lesser BMI increment in a cohort followed for 3.2 years. Similar results were found among Spanish obese adults, with the authors of that study reporting that higher baseline irisin was associated with a greater reduction in body weight [22]. There have been studies examining the relationship between irisin concentration and dynamic changes in the obesity index due to diet, exercise or surgery intervention [16, 22, 23]. To our knowledge, our study is the first study to examine the association between irisin concentration and BMI variation without intervention in a longitudinal study.

Irisin is a myokine that has been found to be effective in inducing browning in white adipose tissue [3]. Adipose tissue browning is accompanied by a higher oxygen consumption, higher energy expenditure and weight loss [3]. In an in vivo study, r-irisin administered to diet-induced obese mice brought about an improvement in body weight and glucose metabolism; in vitro, when r-irisin was added to mouse primary adipocytes, expression of thermogenic genes, such as UCP-1, PGC-1α and Cox7α, and energy consumption were increased [4]. Therefore, it may be postulated that a higher baseline irisin level may prevent an increase in the BMI by inducing more energy expenditure.

Consistent with previous findings [8, 9, 15], our study demonstrated that serum irisin was negatively correlated to the FPG level. Irisin is a C-terminal proteolytical product of FNDC5, encoded by FNDC5, which can be induced in skeletal muscle by PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) by exercise [3]. In our study, serum irisin level was also positively correlated with active physical activity. PGC1α expression was found to be downregulated and the activity of PGC1α to be decreased in the skeletal muscles of patients with T2DM or insulin resistance [24]. In these patients, even increasing exercise cannot stimulate PGC1α expression in skeletal muscles, a condition known as “exercise resistance” [25]. In humans, FNDC5 is mainly expressed in skeletal muscles, followed by lower expression in adipose tissue [6]. Studies have shown that FNDC5 expression in adipose tissue and skeletal muscle was reduced in obese and T2DM patients [8, 26]. It would appear, therefore, that prediabetic or diabetic people have lower serum irisin levels.

There are a number of limitations to our study. First, the sample size of each subgroup was relatively small, and in the longitudinal study, the number of cases was limited to be able to examine the possible predictive role of serum irisin for developing obesity, which was why BMI increment was chosen as primary outcome. Second, although BMI is the most common index defining obesity and overweight, it is a relatively rough measurement and cannot be used to evaluate the degree of obesity with precision. Third, the serum samples used in our present study were collected in 2011. These samples were stored − 80 °C without repeated freezing and thawing for nearly 6 years. To test for degradation, we enrolled ten newly diagnosed T2DM patients hospitalized at the Endocrinology Department of the Affiliated Hospital of Guizhou Medical University in the study and collected fasting blood samples to determine the serum irisin concentration. In our study, ten subjects in the cross-sectional cohort were selected; these subjects were matched to each patient by age and sex to examine whether the irisin molecule was degraded during storage. No significant difference was found between the serum of these two groups.

In conclusion, the innovation of our study is the exploration of the association between serum irisin levels and BMI in a cross-sectional study of Chinese subjects with different BMIs. Our study is also the first longitudinal study in a Chinese population to examine whether serum irisin can predict a change in BMI. We found that baseline serum irisin level had no association with the baseline BMI, but it did play a predictive role in BMI increment. In the future, prospective studies with a larger sample of Chinese subjects are needed to confirm these observations.