Irisin and Its Relation to Insulin Resistance and Puberty in Obese Children: A Longitudinal Analysis

Abstract

Context:

Irisin is a recently identified myokine affecting metabolic and glucose homeostasis. However, the role of irisin in obesity and its metabolic consequences are controversial, and data in children are scarce.

Objective:

To study the relationships between irisin, insulin resistance, and puberty before and after weight loss in obese children with and without impaired glucose tolerance.

Design:

One-year follow-up study in obese children participating in a lifestyle intervention.

Setting:

Primary care.

Patients:

Forty obese children and 20 normal-weight children of similar age, gender, and pubertal stage.

Intervention:

A 1-year outpatient intervention program based on exercise, behavior, and nutrition therapy.

Main Outcomes Measures:

Fasting serum irisin, weight status (body mass index [BMI] SD score), and the following parameters of the metabolic syndrome: insulin resistance index (homeostasis model of assessment), blood pressure, and lipids.

Results:

The irisin levels were the highest in obese children with impaired glucose tolerance, followed by obese children with normal glucose tolerance, and levels were lowest in normal-weight children (P < .001). In a multiple linear regression analysis, baseline irisin was significantly associated with pubertal stage, high-density lipoprotein-cholesterol, and homeostasis model of assessment, but not to age, gender, BMI, or any other parameter of the metabolic syndrome. The irisin concentrations were significantly (P = .010) lower in the prepubertal compared to the pubertal children. In longitudinal analyses, changes of irisin were significantly associated with entry into puberty, change of fasting glucose, and 2-hour glucose in an oral glucose tolerance test, but not with change of BMI or any other parameter.

Conclusions:

Irisin levels are related to pubertal stage and insulin resistance but not to weight status in childhood.

Obesity is a complex disease involving a number of different peptides, transmitters, and their receptors controlling energy homeostasis (1). Both adipose tissue and skeletal muscle have been identified as endocrine organs secreting hormones called adipokines and myokines, respectively (2). It has been proposed that there is muscle-adipose tissue cross talk (3), critical for the regulation of body weight and metabolism, but the specific metabolic pathways and mediators remain elusive.

Irisin, a newly discovered myokine induced by exercise, may contribute to muscle-adipose tissue cross talk (4). Circulating irisin results from C-terminal cleavage of the fibronectin type III domain-containing (FNDC) 5 transmembrane protein, which is the product of the FNDC5 gene (4, 5). This process is induced by the peroxisome proliferator-activated receptor-γ coactivator-1α (4). Irisin, by acting through a currently unknown receptor, increases thermogenesis, possibly improving glucose homeostasis (5–8). Irisin is suggested to induce uncoupling protein 1 and subsequently increase energy expenditure in white adipocytes of rodents, a process called adipocyte browning (4). Furthermore, irisin is suggested to be involved in the pathogenesis of various complications of obesity including dyslipidemia, type 2 diabetes mellitus, and arterial hypertension (9), summarized in the definition of the metabolic syndrome (MetS) (1). Accordingly, circulating irisin concentrations have been reported to be increased in insulin resistance states and MetS (8–11).

However, there are inconsistencies regarding the relevance of irisin in humans, especially in obesity (12). For example, a positive association of irisin levels and body mass index (BMI) was found in some studies (6, 8, 10, 13), whereas other studies reported no correlation between irisin and BMI (14–16) or a negative correlation (7, 9, 10). Furthermore, the few weight loss studies in obese humans have also demonstrated controversial findings reporting decreasing irisin levels in adults (13, 17, 18) and increasing irisin levels in children (19).

Interestingly, there are no studies on the relationship between irisin levels and puberty so far. This is of particular interest because insulin resistance increases with entry into puberty (20, 21). Therefore, one would expect an increase of irisin with entry into puberty if a relevant relationship between irisin and insulin resistance exists in humans.

Given this partially unclear situation in obese humans and no studies concerning the relationship between puberty and irisin levels, we analyzed the long-term changes of irisin levels in obese children with respect to pubertal stage. We also compared irisin concentrations between obese and normal-weight children, studied the effects of weight reduction by a lifestyle intervention, and analyzed the relationships between irisin levels and parameters of the MetS such as insulin resistance, lipids, blood pressure, and impaired glucose tolerance in the course of 1 year. Longitudinal studies and studies in obese children seem preferable because: 1) cross-sectional studies cannot prove causality and are prone to many confounders; 2) adverse patterns of MetS itself begin in childhood; and 3) studies in children have the advantage that there is no potential confusion with other diseases, medications, or active tobacco smoking. We hypothesized that irisin concentrations increase with entry into puberty and are related to insulin resistance and parameters of the MetS. The novelty of our study is the longitudinal analysis of irisin concentrations in obese children participating in a lifestyle intervention analyzing the effect of puberty on irisin concentrations.

Subjects and Methods

Subjects

Written informed consent was obtained from children and their parents. The study was approved by the local ethics committee of the University of Witten/Herdecke in Germany.

We examined 40 obese Caucasian children from our obesity cohort (for details see Ref. 22) and 20 normal-weight children. We decided to evaluate 10 obese children with impaired glucose tolerance at baseline and substantial weight loss after lifestyle intervention, 10 obese children with impaired glucose tolerance at baseline and no weight loss, 10 obese children with normal glucose tolerance at baseline and substantial weight loss, and 10 obese children with normal glucose tolerance at baseline and no weight loss in order to include children with and without weight loss as well as children with and without disturbed glucose metabolism. Substantial weight loss was defined according to BMI-SD score (SDS) reduction > 0.5 according to our previous studies (23, 24). All obese children in the different groups were matched for age, gender, and pubertal stage at baseline.

All 40 obese children participated in the lifestyle intervention “Obeldicks,” which has been described in detail elsewhere (25). Briefly, this outpatient intervention program for obese children is based on physical exercise, nutrition education, and behavior therapy, including the individual psychological care of the child and his or her family. The nutritional course is based on a fat- and sugar-reduced diet as compared to the everyday nutrition of German children.

None of the children in the current study suffered from endocrine disorders, premature adrenarche, or syndromal obesity (for details of the diagnostic procedures, see Ref. 22).

Measurements

We analyzed anthropometrics, pubertal stage, irisin, and the following parameters of MetS: blood pressure, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, glucose, and insulin. These variables were determined at baseline in all children and 1 year later in all obese children after participating in the lifestyle intervention Obeldicks. Furthermore, 2-hour glucose levels were analyzed at baseline and 1 year later in the obese children.

Clinical parameters

Height was measured to the nearest centimeter using a rigid stadiometer. Weight was measured unclothed to the nearest 0.1 kg using a calibrated balance scale. BMI was calculated as weight in kilograms divided by the square of height in meters. The degree of overweight was quantified using Cole's least mean square method, which normalized the BMI skewed distribution and expressed BMI as a SDS (26). Reference data for German children were used (27). All children in the intervention study were obese according to the definition of the International Obesity Task Force (28).

The pubertal developmental stage was determined according to Marshall and Tanner. Pubertal developmental stage was categorized into two groups based on breast and genital stages (prepubertal, boys with genital stage I and girls with breast stage I; and pubertal, boys with genital stage ≥II and girls with breast stage ≥II).

Blood pressure was measured using a validated protocol (29). Briefly, blood pressure was measured at the right arm after a 10-minute rest in the supine position with an oscillometric device (Omron M6; Omron Healthcare). Two recordings were made 5 minutes apart, and the lowest value of the two recordings of systolic and diastolic blood pressure measurements was recorded. The cuff size was based on the length and circumference of the upper arm and was as large as possible without having the elbow skin crease obstructing the stethoscope (29).

Biochemical parameters

Blood sampling was performed in the fasting state at 8 am. After clotting, blood samples were centrifuged for 10 minutes at 8000 rpm. Serum was stored at −81°C for later determination of irisin and insulin. All samples were thawed only once. Irisin levels were measured with a highly specific commercially available ELISA (catalog no. EK-067–29; Phoenix Pharmaceuticals) (sensitivity, 1.29 ng/mL; intra-assay coefficient of variation (CV), 4–8%; interassay CV, 8–12%). Insulin concentrations were measured by microparticle enhanced immunometric assay (Abbott GmbH & Company). Glucose levels were determined by colorimetric test using a Vitros analyzer (Ortho Clinical Diagnostics). Triglycerides and LDL- and HDL-cholesterol were determined by commercially available test kits (Roche Diagnostics). Intra- and interassay CVs were < 5% in all these methods. Homeostasis model assessment (HOMA) was used to detect the degree of insulin resistance using the formula: resistance (HOMA) = (insulin [mU/L] × glucose [mmol/L])/22.5 (30). An oral glucose tolerance test (oGTT) was performed in all obese children according to current guidelines (31). Impaired glucose tolerance (IGT) was defined by 2-hour serum glucose > 140 mg/dL in oGTT.

Statistics

Statistical analyses were performed using the Winstat software package (R. Fitch Software). Normal distribution was tested by the Kolmogorov-Smirnov test. Baseline irisin levels were correlated to anthropometric variables, parameters of the MetS, and insulin resistance index HOMA by Spearman correlation. Changes of irisin levels were correlated to changes of the above-mentioned variables in the 1-year follow-up by Spearman correlation. Changes of puberty were set as 0 for remaining prepubertal or pubertal and 1 for entry into puberty. Furthermore, multiple backward linear regression analyses were calculated with irisin as the dependent variable adjusted to age, gender, and BMI, and the independent variables of blood pressure, triglycerides, HDL-cholesterol, LDL-cholesterol, fasting glucose, insulin, HOMA, and pubertal stage. Because baseline irisin levels were not normally distributed, irisin levels were log-transformed in this analysis. Gender and pubertal stage were used as categorical variables in this model. To compare variables at baseline or in the course of 1 year, Fisher exact test and Student's t test for paired and unpaired observations, Wilcoxon test, Mann-Whitney U test, and Kruskal-Wallis test were used as appropriate. A P value < .05 was considered as significant. Data were presented as mean and SD or median and interquartile range (IQR).

Results

The characteristics of the study cohort are presented in Table 1. The irisin concentrations differed significantly between obese children with and without impaired glucose tolerance and normal-weight children. The irisin levels were highest in obese children with impaired glucose tolerance, followed by obese children with normal glucose tolerance, and were lowest in normal-weight children (Figure 1).

Table 1.

Characteristics of the Study Population at Baseline

	Normal-Weight Children	Children With NGT and No Weight Reduction	Children With NGT and Weight Reduction	Children With IGT and No Weight Reduction	Children With IGT and Weight Reduction	P Value
n	20	10	10	10	10
Age, y	12.3 ± 1.9	13.4 ± 1.7	12.8 ± 1.0	12.5 ± 1.7	12.3 ± 1.9	.875
Gender, male	50%	50%	50%	50%	50%	.999
Pubertal stage	50%	30%	30%	30%	30%	.688
BMI, kg/m2	18.9 ± 2.5	29.6 ± 3.6	30.0 ± 3.8	31.5 ± 5.1	29.7 ± 2.7	<.001
BMI-SDS	0.12 ± 0.69	2.31 ± 0.37	2.38 ± 0.43	2.56 ± 0.45	2.50 ± 0.20	<.001
Systolic BP, mm Hg	112 ± 8	122 ± 15	125 ± 18	123 ± 10	127 ± 14	.015
Diastolic BP, mm Hg	52 ± 5	68 ± 11	74 ± 12	75 ± 8	72 ± 8	<.001
LDL-cholesterol, mg/dL	83 ± 7	87 ± 31	118 ± 46	98 ± 27	104 ± 23	.025
HDL-cholesterol, mg/dL	54 ± 4	54 ± 13	52 ± 7	50 ± 14	47 ± 12	.208
Triglycerides, mg/dL	76 ± 12	94 ± 44	133 ± 52	134 ± 59	135 ± 37	<.001
Fasting glucose, mg/dL	84 ± 3	85 ± 4	83 ± 6	89 ± 7	88 ± 6	.095
2-h glucose, mg/dL	n.d.	105 ± 5	108 ± 14	156 ± 13	155 ± 8	<.001
Insulin, mU/L	5 (3–7)	19 (16–23)	16 (10–26)	38 (20–70)	34 (20–46)	<.001
HOMA	1.2 (0.7–1.5)	4.0 (3.4–4.4)	3.3 (2.1–5.2)	8.6 (4.3–13.7)	7.1 (4.3–9.5)	<.001
Irisin, ng/mL	6.4 (5.7–7.7)	8.3 (6.8–11.2)	10.2 (8.0–11.7)	10.7 (7.2–12.4)	11.2 (9.5–13.1)	<.001

Abbreviations: n.d., not determined; NGT, normal glucose tolerance; IGT, impaired glucose tolerance; BP, blood pressure. Data are expressed as mean ± SD or median (IQR), unless described otherwise. P values are derived from Kruskal Wallis test or Fisher exact test.

Figure 1.

Irisin levels (median, interquartile range, minimum and maximum) in 20 normal-weight children, 20 obese children with normal glucose tolerance, and 20 obese children with impaired glucose tolerance at baseline (median, interquartile range, and range are shown).

P value was derived from Kruskal-Wallis test with Dunn's Multiple Comparison Post Test. **, P < .01; *** P < .001.

At baseline, the 30 boys did not differ significantly (P = .404) with respect to their irisin levels as compared to 30 girls (boys, median irisin levels, 7.7 [IQR, 6.1–11.6] ng/mL; girls, median irisin levels, 9.5 [IQR, 7.1–11.7] ng/mL).

The irisin concentrations differed significantly (P = .010) between the 22 prepubertal (median irisin concentration, 6.8 [IQR, 5.7–11.5] ng/mL) and 38 pubertal children (median irisin concentration, 9.5 [IQR, 7.3–12.2] ng/mL). Analyzing only obese children demonstrated the same findings: the irisin concentrations differed significantly (P = .010) between the 12 obese prepubertal (median irisin concentration, 7.5 [IQR, 5.8–11.5] ng/mL) and 28 obese pubertal children (median irisin concentration, 10.9 [IQR, 9.4–12.8] ng/mL).

Irisin was significantly correlated at baseline with BMI (r = 0.51; P < .001), BMI-SDS (r = 0.53; P < .001), and many parameters of the MetS, such as insulin (r = 0.65; P < .001), 2-hour glucose in oGTT (r = 0.33; P = .020), HOMA (r = 0.65; P < .001), HDL-cholesterol (r = −0.398; P < .001), LDL-cholesterol (r = 0.36; P = .002), triglycerides (r = 0.53; P < .001), diastolic blood pressure (r = 0.38; P = .001), but not significantly with age (r = 0.09), systolic blood pressure (r = −0.16), and fasting glucose (r = 0.06).

In a multiple linear backward regression analysis (r² = 0.28), baseline log-transformed irisin was significantly associated with pubertal stage (β-coefficient, 0.09 ± 0.08; P = .048), HDL-cholesterol (β-coefficient, −0.004 ± 0.003; P = .027), and HOMA (β-coefficient, 0.014 ± 0.012; P = .005), but not to age, gender, BMI, or any other parameter of the MetS. Excluding the parameters of the MetS except HOMA in this model also demonstrated a significant association to pubertal stage (β-coefficient, 0.08 ± 0.07; P = .016) and HOMA (β-coefficient, 0.011 ± 0.009; P = .033), but not to age, gender, or BMI.

In the 1-year follow-up period, the changes of irisin in the obese children correlated significantly with entry into puberty (r = 0.38; P = .009) and change of fasting glucose (r = 0.28; P = .043), but not to changes of BMI, BMI-SDS, or any other parameter of the MetS.

Five obese children entered puberty during the study period. Their irisin levels increased significantly (P = .043) from median 9.1 (IQR, 6.1–10.1) ng/mL to median 12.2 (IQR, 8.9–13.6) ng/mL. In the 35 obese children without change of pubertal stage, the irisin levels remained stable (P = .110) in the study period (median, 10.8 [IQR, 9.2–12.5] ng/mL vs median, 10.0 [IQR, 7.7–11.8] ng/mL).

In a multiple linear backward regression analysis (r² = 0.40), changes of irisin in the 1-year follow-up period were significantly associated with entry into puberty (β-coefficient, 5.2 ± 1.4; P < .001), changes of fasting glucose (β-coefficient, 0.17 ± 0.06; P = .008), and changes of 2-hour glucose in oGTT (β-coefficient, 0.03 ± 0.01; P = .023), but not to age, gender, BMI, changes of BMI, or any other parameter of the MetS. Excluding the parameters of the MetS except changes of HOMA in this model also demonstrated a significant association to pubertal stage (β-coefficient, 0.16 ± 0.07; P = .008), but not to age, gender, BMI, or changes of HOMA or changes of BMI.

In the 20 obese children with substantial reduction of BMI-SDS in the intervention period, most cardiovascular risk factors improved significantly, whereas irisin concentrations did not change significantly (Table 2 and Figure 2). Analyzing only the 10 children with IGT at baseline and substantial weight loss also demonstrated no significant changes of irisin (P = .910). In contrast, the irisin levels increased significantly in the children without weight loss (Table 2) and in the children with IGT and without weight loss (Figure 2).

Table 2.

Changes of Anthropometrics, Irisin, and Parameters of MetS in Obese Children Participating in a 1-Year Lifestyle Intervention

	Obese Children With Substantial Weight Loss			Obese Children Without Weight Loss
	No. of subjects	20			20
Age, y	12.5 ± 1.5			12.9 ± 1.7
Gender, female	50%			50%
Pubertal stage	30%			30%
	Baseline	1 y Later	P Value	Baseline	1 y Later	P Value
BMI, kg/m2	29.9 ± 3.2	26.5 ± 3.0	<.001	30.6 ± 4.4	31.2 ± 4.7	.039
BMI-SDS	2.44 ± 0.33	1.83 ± 0.46	<.001	2.43 ± 0.42	2.46 ± 0.44	.378
Irisin, ng/mLa	10.6 (9.4–12.7)	10.5 (9.1–12.5)	.601	9.2 (7.2–11.8)	10.5 (9.1–12.1)	.025
Systolic blood pressure, mm Hg	126 ± 16	111 ± 10	<.001	123 ± 13	124 ± 12	.789
Diastolic blood pressure, mm Hg	73 ± 10	60 ± 8	<.001	71 ± 10	72 ± 9	.960
LDL-cholesterol, mg/dL	110 ± 36	87 ± 38	.017	92 ± 29	97 ± 23	.472
HDL-cholesterol, mg/dL	50 ± 10	53 ± 12	.096	52 ± 13	50 ± 13	.222
Triglycerides, mg/dL	134 ± 44	75 ± 28	<.001	114 ± 54	125 ± 51	.452
Glucose, mg/dL	85 ± 6	85 ± 7	.948	87 ± 6	87 ± 5	.634
Insulin, mU/La	23 (12–34)	11 (9–13)	<.001	22 (18–39)	22 (14–33)	.794
Insulin resistance index (HOMA)a	4.6 (2.5–8.1)	2.5 (1.9–3.1)	<.001	4.5 (3.7–9.0)	5.1 (3.1–7.2)	.911
2-h glucose in oGTT, mg/dL	131 ± 26	96 ± 10	<.001	130 ± 28	112 ± 21	.100

Data are expressed as percentage or mean ± SD, unless described otherwise.

^a

Not normally distributed, expressed as median (IQR).

Figure 2.

Irisin levels (A; median and interquartile range, minimum and maximum) and BMI-SDS (B; mean and SD) in 40 obese children separated according to glucose tolerance and change of weight status at baseline and 1 year later.

Two statistical analyses were performed: 1) comparison of baseline irisin and BMI-SDS from all four groups, which were not significantly different by Kruskal Wallis test with Dunn's multiple comparison post test; and 2) changes of irisin and BMI-SDS within each group before and after intervention (P values derived from Wilcoxon test for intragroup comparisons are shown).

Discussion

To the best of our knowledge, this is the first study analyzing the longitudinal relationships between irisin, pubertal stage, obesity, and the parameters of the MetS including insulin resistance index HOMA in obese children participating in a lifestyle intervention.

According to most previous studies (8–11, 17, 18, 32–34), irisin was significantly and positively associated to insulin resistance index HOMA and other parameters of the MetS in both cross-sectional and longitudinal analyses of our study. In contrast, one pediatric study reported (35) a negative relationship between HOMA and irisin levels. The reason for this discrepancy remains unclear. Because irisin has been reported to induce glucose and fatty acid uptake in human muscle (7, 36), the increase of irisin in insulin-resistant obese humans in most studies seems to be a state of “irisin resistance.”

At baseline, we found no relationships between the degree of overweight and irisin levels in multiple linear regression analyses, whereas HOMA was significantly associated with irisin concentrations. Furthermore, changes of BMI were not related to changes of irisin levels, suggesting that the univariate significant correlation between weight status and irisin levels in our study was largely mediated by insulin resistance. A too-small amount of weight loss or a too-small study cohort as the explanation for the lack of significance seems unlikely because, according to previous studies (23, 24), a BMI-SDS reduction > 0.5 was associated with an improvement of most cardiovascular risk factors, proving the clinical relevance of the achieved weight loss. These observations are in line with many previous studies demonstrating no positive relationship between BMI and irisin levels (7–10, 13–16). Weight loss studies reporting decreasing irisin levels were based on a short-term hypocaloric diet (8, 13, 17, 18) in contrast to our intervention. It is well known that hypocaloric diet leads to a decrease of lean body mass. Interestingly, lean body mass but not fat mass was a strong positive predictor of irisin levels in a previous study (14). Therefore, in humans irisin seems to be mainly produced by muscle, even if production of irisin in the adipose tissue has been reported (3, 7).

One striking finding of our study was that irisin concentrations were significantly higher in pubertal obese children as compared to prepubertal children. Furthermore, entry into puberty—when insulin resistance physiologically increases (20, 21)—was associated with an increase of irisin levels underlining the relationship between insulin resistance and irisin levels in humans. This increase of irisin in puberty may explain some unexpected and controversial findings concerning irisin levels in children in the literature. Interestingly, the study reporting an increase of irisin after weight loss in obese children due to lifestyle intervention (19) was not adjusted for pubertal changes. Therefore, the reported increase of irisin may also be caused by entry into puberty according to the age range of the analyzed children. Furthermore, in contrast to our analyses and other studies (14, 18, 19), one pediatric study reported higher irisin levels in girls (35). Again, this study did not adjust for pubertal stage, probably explaining this surprising finding, because girls usually enter puberty earlier than boys.

Surprisingly, the increase of irisin in the 1-year observation period in obese children without weight loss was not accompanied by a significant increase of insulin resistance or a significant deterioration of cardiovascular risk factors. One might argue that most cardiovascular risk factors tended to deteriorate and did not reach statistical significance due to the relatively small number of patients. However, the improvement of cardiovascular risk factors and insulin resistance in obese children with weight loss was also not associated with a decrease of irisin. Conversely, the changes in irisin levels were significantly related to changes in glucose metabolism parameters. These controversial findings suggest that irisin levels are also influenced further by factors except glucose metabolism. One possible explanation for these perplexing findings besides other unknown confounders maybe the effect of entry into puberty in the study period, superimposing the relationships between glucose metabolism, cardiovascular risk factors, and irisin levels. For example, entry into puberty is associated with many hormonal changes and changes of body composition.

Our study has a few potential important limitations. First, BMI percentiles were used to classify overweight. Although BMI is a good measure for overweight, one needs to be aware of its limitation because it does not differentiate between body fat and lean body mass. Second, we only divided the children in two stages according to their pubertal stage, probably missing an effect of later pubertal stages on irisin levels. Third, the HOMA model is only an assessment of insulin resistance. Clamp studies are actually the “gold standard” for analyzing insulin resistance. However, validation studies in youth demonstrated a good correlation between HOMA and clamp techniques (37). Fourth, we are not able to differentiate the effect of diet, increased physical exercise, and weight status on irisin concentrations due to our study protocol. This is of special interest because irisin levels are likely related to exercise. Irisin levels were increased immediately after exercise and correlate with exercise intensity (14, 36, 38), but they are unrelated to fitness levels (36). In contrast, irisin levels were not affected by diet (14, 39). Fifth, some studies have questioned whether irisin plays a role in humans, and a large portion of this controversy is accounted for due to the use of different assay kits (12). Our test kit has been successful in detecting changes in irisin levels in the circulation (8, 9). Another reason for the inconsistency could be the differences in study design and lack of prior knowledge on the timeframe over which irisin is increased. For example, irisin displays a day-night rhythm irrespective of physical activity (14). In our study, irisin was always measured at the same time, 8 am. Sixth, the number of children in the different obesity group (substantial weight loss, yes/no; impaired glucose tolerance, yes/no) was small, probably missing significant relationships. Finally, because we studied children and age is a well-recognized parameter that clearly contributes to insulin resistance and the MetS severity, all statements can be applied only to children and not to adults. We found no effect of age on irisin levels according to other studies in young humans (14, 19, 36), whereas decreasing irisin levels with age have been reported in older adults (8, 36), probably due to lower physical activity in this age range.

In summary, this is the first study in childhood demonstrating that irisin levels are associated to pubertal stage. The increase of irisin levels in obesity was largely determined by insulin resistance. Because irisin concentrations were positively related to insulin resistance and parameters of MetS, we put forward the hypothesis that obese children with features of the MetS are in an irisin-resistant state.

Acknowledgments

T.R. and C.L.R. developed the study design. T.R. and N.L. performed the anthropometrical measurements. C.L.R. and C.E. performed the laboratory measurements. All authors discussed the findings, and T.R. wrote the first draft of the paper.

This study is registered at clinicaltrials.gov (NCT00435734).

Disclosure Summary: The authors have nothing to disclose.

Abbreviations

 
• BMI

  body mass index

 
• CV

  coefficient of variation

 
• HDL

  high-density lipoprotein

 
• HOMA

  homeostasis model assessment

 
• IGT

  impaired glucose tolerance

 
• IQR

  interquartile range

 
• LDL

  low-density lipoprotein

 
• MetS

  metabolic syndrome

 
• oGTT

  oral glucose tolerance test

 
• SDS

  SD score.