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Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity
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European Neuropsychopharmacology (2018) 000, 1–11
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Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity Ge Li a,1, Dan Feng b,1, Xiaoxue Qu b, Junling Fu a, Yonghui Wang b, Lianxia Li b, Lujiao Li a, Lanwen Han b, Issy C. Esangbedo c, Mingyao Li d, Ming Li a,2,∗, Shan Gao b,2,∗ a
Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China b Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, China c Health Weight Program, The Children’s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, PA 19104, USA d Departments of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA Received 6 January 2017; received in revised form 24 February 2018; accepted 21 May 2018 Available online xxx
KEYWORDS Adipokine; Self-concept; Youths; Obesity
Abstract The mechanisms by which obesity increases the risk of psychosocial disorders remain unclear. We aimed at exploring the association between obesity and self-concept in Chinese youths and the role of adipokines. Data for 559 participants (aged 14–28 years) were analyzed. Self-concept was assessed by utilizing the Self-Description Questionnaire II (SDQ-II). Subjects with obesity had higher leptin, FGF21 and lower adiponectin levels (all p < 0.001). They also had lower SDQII scores especially in the domains of general school, physical abilities, physical appearance and opposite-sex relations (all p < 0.001). Both elevated FGF21 and leptin were correlated with lower scores in math (p < 0.01), physical abilities (p < 0.01), and opposite-sex relations (p < 0.05), meanwhile FGF21 negatively correlated with the scores in general school and hon-
∗ Corresponding
authors. E-mail addresses: [email protected], [email protected] (M. Li), [email protected] (S. Gao). 1These authors share co-first authorship. 2These authors contributed equally to this work. https://doi.org/10.1016/j.euroneuro.2018.05.015 0924-977X/© 2018 Elsevier B.V. and ECNP. All rights reserved.
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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G. Li et al. esty/trustworthiness, and leptin negatively correlated with physical appearance (p < 0.01) but positively with verbal (p < 0.01). In contrast, decreased adiponectin was correlated with poorer physical abilities (p < 0.05), physical appearance (p < 0.05), and parent relations (p < 0.01). Moreover, these associations of leptin, FGF21 and adiponectin with certain domains remained significant after adjustment for BMI and other metabolic confounders. In conclusion, youths with obesity experienced poorly on self-concept, and these associations may be explained in part by adipokines leptin, FGF21 and adiponectin. © 2018 Elsevier B.V. and ECNP. All rights reserved.
1.
Introduction
The increasing worldwide prevalence of obesity in youths is one of the most challenging healthcare problems (Ng et al., 2014). While the physical effects of overweight in youth have been widely documented (Schmidt, 2015), less is known about the psychosocial burden of excess weight, and what is known is largely confined to isolated aspect of psychosocial function such as low self-esteem, depression or body dissatisfaction (Pulgaron, 2013). Moreover, the mechanisms by which obesity increases risk of psychosocial disorder remain unclear (Pulgaron, 2013). It is now widely recognized that adipose tissue is hormonally active, secreting a wide range of peptides known as adipokines, which regulate important physiologic processes in target organs including not only liver, muscle, heart and immune system, but also brain (Fasshauer and Bluher, 2015). In obesity, the adipose tissue dysfunction leads to altered adipokines secretion, therefore contributes towards cardio-metabolic diseases (Bluher and Mantzoros, 2015 and Fasshauer and Bluher, 2015). However, whether adipokines could link available energy stores with psychosocial conditions has rarely been addressed. Self-concept plays an important role in psychosocial assessment. The development of negative beliefs about self can result in maladaptive responses and mental states. The association between obesity and self-concept among youths is still being debated. While some investigations observed that the degree of overweight was significantly associated with evaluation of physical appearance (Danielsen et al., 2012), other studies have not observed a relationship with self-esteem (Young-Hyman et al., 2003). To date, few studies have been conducted to explore multiply domains of self-concept based on large samples in youths with overweight and obesity, and study of the potential mechanisms of obesity on self-concept is still lacking, especially in Chinese population (Chung et al., 2015). Recent studies showed that association between obesity and neurodegenerative diseases could be mediated by the pleiotropic effects of adipokines, particularly by those adipokines which may function through central nervous system (CNS), such as leptin (Dalamaga et al., 2013), adiponectin (Arnoldussen et al., 2014) and FGF21 (Leng et al., 2015). Additionally, Nixon Nixon Andreasson et al. (2010) found that elevated leptin correlated with poor existing self-rated health in men. Based on these recent findings, we therefore hypothesized that the effects of obesity on psychosocial disorders might also be mediated by the dysregulation of those adipokines with established CNS actions. Since the Self-Descriptive
Questionnaire II (SDQ-II) is a leading multidimensional self-concept instrument for adolescents and used widely (Hau et al., 2003 and Marsh, 1990), we aimed to determine the association between obesity and self-concept measured by SDQ-II in Chinese youths based on a large cohort of Beijing Child and Adolescent Metabolic Syndrome Study (BCAMS) (Li et al., 2009 and Wang et al., 2013). Furthermore, we sought to investigate the levels of three adipokines including leptin, adiponectin and FGF21 in obesity, as well as their roles in linking obesity with self-concept.
2. 2.1.
Experimental procedures Participants
Subjects were recruited from the cohort of BCAMS study (Li et al., 2009 and Wang et al., 2013). The BCAMS study evaluated the prevalence of obesity and related metabolic abnormalities including hypertension, hyperglycemia and dyslipidemia in Beijing school-age children (n = 19,593, age 6–18 years, 50% male) from April to October 2004. 4,500 participants were identified as being at high risk due to having one of the followings: overweight defined by body mass index (BMI), elevated cholesterol ≥ 5.2 mmol/l, elevated triglycerides (TG) ≥ 1.7 mmol/l or elevated fasting glucose ≥ 5.6 mmol/l based on finger capillary blood tests. Follow-up study for the BCAMS cohort started in 2012 (Fu et al., 2016). Participants were recruited consecutively through various modalities and underwent medical examination at the healthcare center of Beijing Chaoyang Hospital. Informed consent was obtained from all participants and/or their parents or guardians through all the study processes. The protocol for the follow-up examination was approved by the Ethics Committee at the Beijing Chaoyang Hospital. A total of 559 subjects who completed medical examination and questionnaires were included in the current study.
2.2.
Clinical measurements
Height, weight, and waist circumference (WC) were measured by trained field workers. Participants removed bulky clothing and shoes prior to measurements. Height and WC were measured to the nearest 0.1 cm using a portable stadiometer. WC was measured midway between the lowest rib and the top of the iliac crest. Weight was measured to
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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3 the nearest 0.1 kg using a TANITA Body Composition Analyser (Model TBF-300A, Tanita, Japan). Measurements of right arm systolic and diastolic blood pressure (SBP and DBP) were performed three times, 10 minutes apart and the mean values of the latter two measurements were recorded. BMI was calculated as weight divided by height squared. Subjects with ages below 18 years were classified as overweight, if BMI was between the 85th and 95th percentile, or obesity if BMI was above 95th percentile. Subjects older than 18 years were classified as overweight if BMI ≥ 24 kg/m2 , or obesity if BMI ≥ 28 kg/m2 .
2.3.
Laboratory measurements
A 2 h oral glucose tolerance test (OGTT) using 75 g oral glucose load was performed on each subject in the morning after 10 h of fasting. With the Hitachi 7060 C automatic biochemistry analysis system, blood glucose levels were measured by hexokinase method at fasting and 2 h post-prandial, the concentrations of TG, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were assayed using a standard enzymatic method, and high-density lipoprotein cholesterol (HDL-C) was assessed using precipitate with phosphotungstic acidMg method. High-sensitivity C-reactive protein (hs-CRP) was measured by immunoturbidimetric assay. Insulin, leptin, and adiponectin were measured by sandwich enzymelinked immunosorbent assay, which was developed in the Key Laboratory of Endocrinology, Peking Union Medical College Hospital (Li et al., 1997; 2008 and 2012). FGF21 was measured by Human Quantikine ELISA Kit (R&D Systems, Inc.)(Fu et al., 2016). The intra-assay coefficient of variations (CVs) for insulin, leptin, adiponectin and FGF21 were < 4.1%, < 7.4%, < 5.4%, and < 4.8%, respectively. The inter-assay CVs were < 7.0%, < 9.3%, < 8.5% and < 7.4%, respectively. Insulin resistance was assessed by the homeostasis model assessment (HOMA-IR), calculated as fasting insulin (μIU/ml) × fasting glucose (mmol/l)/22.5 (Matthews et al., 1985).
2.4.
Self-concept
The Chinese version of the SDQ-II questionnaire was used to assess self-concept (Marsh, 1990). SDQ-II was chosen because its development is based on a multi-dimensional theory of self-concept for adolescents, its language and answer format were relatively easy to understand, and it was translated into Chinese and validated for Chinese population (Hau et al., 2003). The SDQ-II consists of 102 questions which comprise 11 multi-item scales: three components of academic self-concept (math, verbal and general school), seven components of non-academic self-concept (physical abilities, physical appearance, parent relations, oppositesex relations, same-sex relations, honesty/trustworthiness and emotional stability), and a global component (general self). Each of the items is a simple declarative statement, the response to which is made on a 6-point scale (1–6 in ascending order of assessment as true).
2.5.
Statistical analyses
Analyses were performed using the Statistical Package for Social Sciences (SPSS 19.0 for Windows, SPSS Inc., USA). Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Non-normal distribution values such as insulin, leptin, adiponectin, FGF21, and HOMA-IR were natural log-transformed (ln) to comply with the normality assumption. Comparisons between groups were conducted using the analysis of variance or general linear model adjusted for age and sex for continuous variables, while categorical variables were analyzed using the Chi-square test. Partial correlation test and multiple linear regression were used to verify possible association between SDQ and obesity indexes, adipokines and metabolic parameters after adjusted for age and gender, and additional covariates when necessary. Level of significance was accepted as p < 0.05 (two sided).
3.
Results
3.1. The general characteristics of the study population The clinical, biochemical features and SDQ scores of the participants stratified by BMI are shown in Table 1. Among the 559 participants, 265 (47.4%) were female. The mean age of all participants was 20.2 years (14–28 years). In this study, 243 (43.5%) had normal weight, 135 (24.1%) were overweight and 181 (32.4%) were obese by their BMI. When comparing to normal weight and overweight peers, obese participants had higher WC, SBP, DBP, TG, LDL-C, HOMAIR, hs-CRP, fasting insulin and lower level of HDL-C (all p < 0.01). As for adipokines, the comparisons of leptin, adiponectin and FGF21 levels in different body weight categories after controlling for age and sex were showed in Fig. 1. As expected, increasing degree of overweight was significantly associated with elevation in leptin and FGF21, but reduction in adiponectin (all p < 0.001). Regarding self-concept, participants with obesity scored lower in general school, physical abilities, physical appearance and opposite-sex relations domains than both normal weight and overweight subjects (all p < 0.001). Additionally, there were marginal significant differences in same-sex relations (p = 0.050) and honesty/trustworthiness (p = 0.059). However, for verbal, parent relations, and emotional stability domains, there were no group differences (p > 0.05). Notably, even in the overweight group, lower scores in the physical appearance (p < 0.01) and opposite-sex relations (p < 0.05) were observed when compared to their normal weight peers, whereas in same-sex relations and general self domains, the significant difference was observed only between the obesity and normal weight groups.
3.2. Relationship between self-concept and adiposity indexes, adipokines and metabolic parameters After adjustment for age and sex, the correlations observed among adiposity indexes, adipokines, metabolic
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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Table 1
The characteristics of the study population. Total
Normal
Overweight
N (female %) 559(47.4%) 243(59.7%) 135(44.4%) Age (yrs) 20.2(2.9) 20.2(2.9) 20.2(3.1) BMI (kg/m2 ) 25.7(5.7) 20.6(2.1) 25.9(1.3)∗∗ WC (cm) 85.4(14.6) 73.0(6.9) 86.5(7.0)∗∗ SBP (mmHg) 115(14) 107(12) 115(10)∗∗ DBP (mmHg) 73(10) 68(9) 73(8)∗∗ TG (mmol/L) 1.13(0.83) 0.85(0.41) 1.11(0.70)∗∗ TC (mmol/L) 4.35(0.92) 4.18(0.89) 4.38(0.92) LDL-C (mmol/L) 2.53(0.79) 2.25(0.72) 2.60(0.71)∗∗ HDL-C (mmol/L) 1.44(0.32) 1.57(0.32) 1.41(0.32)∗∗ Fasting glucose (mmol/L) 4.92(0.69) 4.88(0.75) 4.86(0.35) 2h-glucose (mmol/L) 6.06(1.84) 5.94(2.19) 5.85(1.08) HbA1C (%) 5.38(0.48) 5.36(0.49) 5.33(0.29) Fasting insulin (mU/L)& 6.96(2.10) 4.57(1.86) 6.69(1.77) ∗∗ HOMA-IR 2.04(1.92) 1.25(1.34) 1.70(0.95)∗ Hs-CRP (mg/L) 1.81(2.54) 1.02(2.03) 1.80(2.31)∗∗ Self-description questionnaire scores (age- and sex- adjusted mean and s.e.m) Verbal 4.1(1.0) 4.0 (1.0) 4.1 (1.1) Math 3.9(1.2) 4.0 (1.2) 3.8 (1.2) General school 4.4(0.8) 4.5(0.7) 4.5(0.8) Physical abilities 3.8(1.1) 4.0(1.1) 3.9(1.2) Physical appearance 4.1(0.8) 4.4(0.7) 4.1(0.7)∗∗ Opposite-sex relations 4.3(0.8) 4.5(0.8) 4.3(0.9)∗ Same-sex relations 4.9(0.7) 5.0(0.6) 4.9(0.6) Parent relations 4.7(0.8) 4.7(0.8) 4.7(0.7) Honesty/trustworthiness 4.5(0.7) 4.5(0.6) 4.5(0.6) Emotional stability 4.0(0.8) 4.0(0.7) 3.9(0.8) General self 4.7(0.7) 4.7(0.7) 4.7(0.8)
Obesity
p-Value
181(33.1%) 20.1(2.9) 32.4(3.7)∗∗, ## 100.7(10.8)∗∗, ## 124(14)∗∗, ## 80(10)∗∗, ## 1.54(1.12)∗∗, ## 4.55(0.92)∗∗ 2.86(0.80)∗∗, ## 1.27(0.23)∗∗, ## 5.02(0.79) 6.38(1.76)∗, # 5.45(0.57) 12.55(1.78)∗∗, ## 3.36(2.38)∗∗, ## 2.89(2.89)∗∗, ##
<0.001 0.963 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.065 0.018 0.050 <0.001 <0.001 <0.001
4.1 (0.9) 3.8(1.2) 4.2(0.8)∗∗, ## 3.4(1.1)∗∗, ## 3.6(0.8)∗∗, ## 4.1(0.8)∗∗ 4.8(0.6)∗ 4.6(0.8) 4.4(0.6) 4.0(0.8) 4.6(0.7)∗
0.712 0.116 <0.001 <0.001 <0.001 <0.001 0.050 0.305 0.059 0.438 0.019
Data are the means (SD) or n%; Abbreviations: BMI = body mass index; WC = waist circumference; HOMA-IR = insulin resistance index; SBP = systolic blood pressure; DBP = diastolic blood pressure; TG = triglycerides; TC = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = highdensity lipoprotein cholesterol; Hs-CRP = high-sensitivity C-reactive protein; FGF21 = fibroblast growth factor 21. Values in bold are significant at p < 0.05. & Data was antinatural logarithmic transformed when in analyses. ∗ p < 0.05, ∗∗ p < 0.01, compared with normal; # p < 0.05, ## p < 0.01, compared with overweight.
parameters and SDQ scores were shown in Table 2. In this analysis, except for domains in parent relations, honesty/trustworthiness and emotional stability, all the six domains including math, general school, physical abilities, physical appearance, opposite-sex relations and general self were negatively correlated with BMI and WC (all p < 0.05), while verbal was positively correlated with obesity index. In addition, as expected, greater BMI and WC were associated with higher FGF21 and leptin, and lower adiponectin (all p < 0.01). On the other hand, higher FGF21 was significantly correlated with decreased self-concept in math (r = −0.124, p < 0.01), general school (r = −0.111, p < 0.05), physical abilities (r = −0.225, p < 0.01), opposite-sex relations (r = −0.113, p < 0.05) and honesty/trustworthiness (r = −0.093, p < 0.05) domains. Leptin also showed the similar correlation in math (r = −0.138, p < 0.01), physical abilities (r = −0.307, p < 0.01) and opposite-sex relations (r = −0.141, p < 0.01), plus inverse correlation
with physical appearance (r = −0.255, p < 0.01), and positive with verbal (r = 0.183, p < 0.01). Unlike those two adipokines, adiponectin was positively correlated with scores in physical abilities (r = 0.100, p < 0.05), physical appearance (r = 0.117, p < 0.05), and parent relations (r = 0.139, p < 0.01). Notably, further adjustment of BMI attenuated most of these associations; however, FGF21 remained significantly correlated with selfconcept in general school (p < 0.05), physical abilities (p < 0.01) and honesty/trustworthiness (p < 0.05) domains, while leptin remained associated with physical abilities (p < 0.001), and adiponectin remained associated with parent relations (p < 0.05). Additionally, we found several classical cardio-metabolic risk factors were associated with certain domains in self-concept, such as blood pressure, fasting insulin, HOMA-IR, HDL-C and TG. In the emotional stability domain, there was no significant correlation among the variables analyzed in this study.
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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Partial correlation between PSDQ and adiposity index, adipokines and metabolic parameters. BMI
FGF21∗
Adiponectin∗
Leptin∗
SBP
DBP
FBG
FINS∗
TG∗
HDL-C
0.916## / 0.101# −0.141## −0.136## −0.286## −0.324## −0.136## −0.089# −0.028 −0.05 −0.046 −0.113#
0.324## 0.321## 0.055 −0.124## −0.111# −0.225## −0.075 −0.113# −0.044 −0.05 −0.093# −0.03 −0.066
−0.374## −0.356## −0.082 0.044 −0.018 0.100# 0.117# 0.051 0.042 0.139## 0.055 0.041 0.001
0.733## 0.712## 0.183## −0.138## −0.09 −0.307## −0.255## −0.141## −0.055 −0.026 −0.019 −0.028 −0.058
0.529## 0.527## 0.093 −0.101# −0.084∗ −0.146## −0.200## −0.055 −0.073 −0.011 −0.022 −0.009 −0.094
0.482## 0.463## 0.079 −0.182## −0.124## −0.165## −0.114# −0.081 −0.069 0.015 −0.006 0.018 −0.085
0.063 0.074 0.035 −0.109# −0.07 −0.016 0.022 0.006 0.013 0.047 −0.006 0.052 −0.016
0.643## 0.604## 0.190## −0.136## −0.086 −0.238## −0.263## −0.101# −0.085 −0.06 −0.021 −0.045 −0.072
0.293## 0.303## 0.015 −0.081 −0.053 −0.048 −0.097# −0.028 0.028 −0.028 −0.039 0.039 −0.025
−0.337## −0.285## −0.039 0.058 0.049 0.154## 0.128## 0.106# 0.074 0.094# 0.026 0.044 0.118#
/ −0.068 −0.073 −0.059 −0.056 −0.007 0.052 0.024 −0.00001 −0.054 0.027 −0.028
0.076 0.002 −0.079 −0.105# −0.170## 0.024 −0.049 −0.019 −0.041 −0.096# −0.015 −0.059
−0.023 −0.022 −0.028 −0.065 −0.027 0.011 −0.023 −0.023 0.104# 0.043 0.012 −0.034
0.172## 0.081 −0.058 0.002 −0.144## 0.015 0.005 0.052 0.029 −0.017 0.010 0.019
0.108# 0.005 −0.028 −0.019 −0.023 −0.019 0.018 −0.034 −0.023 −0.029 0.036 −0.030
0.056 0.031 −0.127## −0.053 −0.045 0.057 −0.027 −0.035 0.011 0.035 0.022 −0.028
0.029 0.030 −0.089# −0.067 −0.014 0.047 0.020 0.027 0.029 −0.036 0.045 −0.007
0.055 0.115## −0.049 −0.023 −0.105# −0.042 0.018 −0.011 −0.033 −0.036 −0.002 0.0005
0.102# −0.019 −0.022 −0.018 0.001 0.003 0.029 0.050 −0.013 −0.040 0.055 −0.006
0.035 0.032 0.002 −0.010 0.080 0.006 0.019 0.059 0.078 0.002 0.002 0.076
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Age- and sex-adjusted BMI / WC 0.916## Verbal 0.143## Math −0.113# General school −0.108# Physical abilities −0.284## Physical appearance −0.353## Opposite-sex relations −0.175## Same-sex relations −0.114# Parent relations −0.027 Honesty/trustworthiness −0.026 Emotional stability −0.056 General self −0.101# Age-,sex- and BMI- adjusted WC / Verbal / Math / General school / Physical abilities / Physical appearance / Opposite-sex relations / Same-sex relations / Parent relations / Honesty/trustworthiness / Emotional stability / General self /
WC
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Data are the partial correlation coefficient. Abbreviations: BMI = body mass index; WC = waist circumference; SBP = systolic blood pressure; DBP = diastolic blood pressure; TG = triglycerides; HDL-C = high-density lipoprotein cholesterol; FBG = fasting blood glucose; FINS = fasting insulin; FGF21 = fibroblast growth factor 21. Values in bold are significant at p < 0.05. ∗ natural logarithmic transformed when in analyses. # p < 0.05, ## p < 0.01.
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Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
Table 2
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G. Li et al. Fig. 1 FGF21, adiponectin, and leptin levels according to body weight status. Data were shown as means ± s.e.m. FGF21, adiponectin, and leptin levels were natural logtransformed when in analyses. p values were calculated from general linear regression model with post hoc comparisons after controlling for age and gender.
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To further assess the independent role of adipokines in self-concept, a number of regression analyses were conducted by adding all the significantly associated variables (including demography-, adiposity-, and metabolic- variables as shown in Table 2 into the models for each domain. Thus, except for age and gender, Table 3 presents all variables that were entered initially for stepwise regression for those variables that remained significant in the final mode for each domain. As shown in Table 3, after controlling for adiposity and other metabolic confounders, both elevated FGF21 (β = −0.163, p < 0.001) and leptin (β = −0.326, p < 0.001) could independently predict lower physical abilities. In addition, higher FGF21 independently predicted lower general school (β = −0.083, p = 0.004) and honesty/ trustworthiness (β = −0.059, p < 0.05), while increased leptin was associated with decreased math (β = −0.165, p = 0.001), and decreased adiponectin was associated with worse parent relations (β = 0.149, p = 0.004). The important correlations between above-noted adipokines and domains of self-concept were also shown in Fig. 2. These results indicated that increased leptin and FGF21 and decreased adiponectin were the independent mediators of self-concept in some domains.
4.
Discussion
The main finding of the study was that the adolescents and young adults with obesity had lower SDQ-II scores compared to non-obese groups, especially in the general school, physical abilities, physical appearance and opposite-sex relations domains. Adiposity measures, blood pressure, fasting glucose, insulin, TG, HDL-C and three adipokines were correlated with SDQ-II scores. Moreover, the associations between SDQ-II scores and adipokine leptin, FGF21 and adiponcectin were attenuated but remained significant for certain domains after adjusting for BMI, suggesting that these adipokines might be the potential mediators implicated in obesity related self-concept. To the best of our knowledge, this is the first study that provides information about the mediating role of such adipokines in self-concept, especially in Chinese youth. The consequences of obesity are far reaching, not only including health-related physical outcomes, but also psychological, social and behavioral consequences. In agreement with previous studies (Reinehr et al., 2012 and Steinberger et al., 2009), we found that participants with obesity had high blood pressure, high TG, TC, LDL-C, low HDL-C, and adverse profile of adipokines including high leptin, FGF21 and low adiponectin. Since obesity has become a focus for preventative and management action, adolescents’ psychological state has come under increasing attention. Self-concept has been broadly studied since its first theoretical definitions. Self-concept, broadly defined, is a person’s perception of him- or herself. These perceptions are formed through experience with and interpretations of one’s environment. They are influenced especially by evaluations, by significant others, reinforcements, and attributions for one’s own behavior (Shavelson et al., 1976). Currently, there is no universal method to assess the self-concept. SDQ-II is considered a multi-dimensional instrument to assess self-concept for adolescents, which has been validated
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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7 Table 3 Stepwise regression analysis for adiposity-, adipokines- and metabolic variables with each selected domain of selfconcept. Domain Math General school Physical abilities Physical appearance Opposite-sex relations Same-sex relations Parent relations Honesty/trustworthiness
Variables ∗
Leptin DBP FGF21∗ Leptin∗ FGF21∗ BMI BMI BMI Adiponectin∗ FGF21∗
β
STD β
t
P
−0.165 −0.025 −0.083 −0.326 −0.163 −0.051 −0.026 −0.010 0.149 −0.059
−0.143 −0.216 −0.123 −0.300 −0.162 −0.365 −0.179 −0.086 0.123 −0.101
−3.313 −3.418 −2.889 −7.180 −3.865 −9.029 −4.176 −1.988 2.860 −2.380
0.001 0.001 0.004 <0.001 <0.001 <0.001 <0.001 0.047 0.004 0.018
Data was adjusting for age, sex, BMI/WC and other related variables according to Table 2. Abbreviations: BMI = body mass index; WC = waist circumference; FGF21 = fibroblast growth factor 21; DBP = diastolic blood pressure. Values in bold are significant at p < 0.05. ∗ natural log-transformed when in analyses. STD β indicates standardized regression coefficient
in Chinese population (Hau et al., 2003). In this study, we observed that compared to normal weight group, obese group had lower SDQ-II scores indicating that they had serious doubts about their self-worth and lacked confidence. Similar to our results, in a study of Hong Kong children, Sung et al. (2005) observed that overweight children perceived themselves to have poorer appearance, sports competence, overall physical self-concept and self-esteem than normal weight children using physical self-descriptive questionnaire. In another study consisting of 263 Cree schoolchildren in Canada, Willows et al. (2013) reported that children with greater adiposity had lower scores for global self-concept, the intellectual and school status and physical appearance domain of self-concept, which was consistent with our results. In addition, our study revealed that overweight and obese participants scored lower in opposite-sex relations, which was consistent with Gibson’s observation in Australian children (Gibson et al., 2008). Taken together, those previous studies and ours revealed that obese youths exhibited poor self-concept among different races, even though the age distribution, sample size or/and measures of psychosocial functioning varied between studies. The underlying mechanisms with these associations are unclear. However, it is known that a number of adipokines, such as leptin, adiponectin and FGF21, interact directly with specific nuclei in certain areas of the brain (Arnoldussen et al., 2014 and Leng et al., 2015). Adipose tissue dysfunction and adipokine secretion dysregulation is frequently found to accompany obesity. This results in dysregulation of not only metabolism, but also neurodegeneration, synaptic plasticity, neurogenesis and memory consolidation (Bluher and Mantzoros, 2015; Dalamaga et al., 2013 and Fasshauer and Bluher, 2015), suggesting those adipokines might be the potential link between excess of obesity and psychosocial conditions. As we predicted, in our study, elevated leptin and FGF21, and decreased adiponectin were found to be associated with the degree of obesity. Further, with the increase in leptin or FGF21 levels and a decrease in adiponectin, SDQ-II scores were significantly decreased in several domains. Notably, the predicting role of FGF21 for general school, physical
abilities and honesty/trustworthiness, and leptin for physical abilities and math, and adiponectin with parent relation remained evident even after adjusting for BMI as well as other obesity-related metabolic parameters. This suggests that those adipokines might play an important role in mediating obesity and self-concept. Leptin is the first discovered adipokine and has an important role in the regulation of appetite, food intake, and energy expenditure, thus known as the “anti-obesity hormone”. However, the levels of leptin generally parallel the amount of adipose tissue present, and obesity is generally associated with elevated circulating levels of leptin, presumably a marker of leptin resistance (Fasshauer and Bluher, 2015). In addition, studies showed that leptin had neuroendocrine function, leptin may act as a ‘‘master switch’’ for the hypothalamic neuroendocrine axes by binding to its receptors located throughout the CNS. This results in regulation of not only metabolism, growth, and reproduction, but also neurodegeneration, synaptic plasticity, neurogenesis and memory consolidation (Dalamaga et al., 2013). A research in Sweden revealed that higher levels of leptin were associated with poor self-rated health in men in crosssectional analysis when controlling for age and BMI (Nixon Andreasson et al., 2010). A study in Japanese men (Otsuka et al., 2006) observed that individuals who perceived higher stress had increased leptin levels, thus leptin resistance of the hypothalamus may be involved in the pathogenesis of this inability of leptin to affect hypothalamic-pituitaryadrenal (HPA) axis activity. As mentioned above, we found that participants who had higher leptin scored lower in four out of six BMI/WC-related domains including math, physical abilities, physical appearance and opposite-sex relations. Moreover, the reverse association of leptin with math and physical abilities domains remained significant when controlling for BMI or WC. These outcomes revealed that the presence of leptin resistance in obesity may contribute to the decreased self-concept. FGF21 is a member of the FGF superfamily that is predominantly produced by the liver and adipose tissue and acts like a hormone that is critical for regulation of glucose and lipid metabolism, and thus a potential novel drug
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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Fig. 2 Scatter-plot of each selected domain of self-concept and adipokine levels. X-axis represents the adipokine levels and Y- axis represents each selected domain of selfconcept. p value and β for the adipokines in the liner regression model were adjusted for age, sex, body mass index/ waist circumference, and other related variables according to Table 2. FGF21, adiponectin, and leptin levels were natural log-transformed when in analyses. Lines are derived from linear regression models.
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9 target for treating diabetes (Fasshauer and Bluher, 2015 and Gaich et al., 2013). Notably, like leptin, FGF21 can cross the blood-brain barrier (Hsuchou et al., 2007 and Tan et al., 2011) and thereby act in the CNS to induce sympathetic nerve activity, energy expenditure and weight loss (Owen et al., 2014), and enhance hepatic gluconeogenesis through activation of the HPA (Bookout et al., 2013 and Potthoff and Finck, 2014). However, as demonstrated by our study, plasma concentrations of FGF21 were found to be elevated in individuals with obesity (Dushay et al., 2010 and Fasshauer and Bluher, 2015), suggesting the existence of a postulated FGF21-resistant state in humans. Interestingly, our study also showed that elevated FGF21 was correlated with decreased levels of obesity-related self-concept, especially in general school and physical abilities domains, and these associations remained significant even after adjusted for BMI and other related metabolic factors. Similar to leptin, this also suggests that the presence of resistance in CNS or compensatory response might contribute to obesity-related decrease of academic and non-academic self-concept. Therefore, improving the leptin and FGF21 resistance in obese youths can not only benefit their metabolic outcomes but also has the potential to improve their psychological, social and behavioral consequence. Given that the CNS is likely a significant target for the potential benefits of FGF-21 in the treatment of diabetes and obesity (Leng et al., 2015), there is a great deal of value to investigate its treatment function in psychological disorders. Adiponectin is almost exclusively produced by adipocytes. In addition to beneficial peripheral effects on insulin sensitivity, anti-inflammatory, and antiapoptotic properties, it also acts in the brain to increase energy expenditure and may promote weight loss (Fasshauer and Bluher, 2015). Unlike leptin and FGF21, circulating adiponectin levels were decreased in multiple metabolic disorders including obesity and related diseases (Bluher and Mantzoros, 2015). In this study, we also found that adiponectin was inversely related to obesity, and its decreased levels were associated with lower self-concept, especially in physical abilities and appearances, and parent relations. Since decreased adiponectin serum concentrations have been found to be associated with mild cognitive impairment and Alzheimer’s disease (Teixeira et al., 2013), thus it might be that the adjustment function of CNS also contributes to its connection with obesity-related self-concept. Strengths of our study include the well-characterized cohort and the novel finding that obesity related self-concept may be partially mediated by adipokines: leptin, FGF21 and adiponectin. Our study also has methodological limitations. First, the sample size is relatively small, which, however, provided more than 80% power to detect significant associations at the r = 0.20 at the conventional p < 0.05 level. Second, the questionnaire of SDQ-II is suitable for adolescents, but youth adults were also included in our study, although similar results were found when analyses were stratified by adolescents and youth adults. Third, the participants are at risk for metabolic syndrome and the frequency of metabolic disorders could be higher than the general population, thus our finding may not be simply generalized to other populations. Future studies with larger sample sizes and validating in various populations will be needed.
In conclusion, we found that youths with obesity in this Chinese population experienced poorly on self-concept, and it might be partially mediated by adipokines: leptin, adiponectin and FGF21. Since increased leptin and FGF21, and decreased adiponectin levels were found to be involved in this process, our results suggest that intervention by improving the sensitivity of leptin and FGF21, and increasing the levels of adiponectin in these youths might benefit not only the metabolic outcomes, but also the psychological, social and behavioral consequences. Future work should focus on applying longitudinal and experimental designs to assess causality.
Acknowledgments We gratefully thank all the participants in the “Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study”.
Role of the funding source This work was supported by key program of Beijing Municipal Science &Technology Commission (D111100000611001); National Key Research program of China (2016YFC1304800); Beijing Science & Technology Star Program (2004A027); Novo Nordisk Union Diabetes Research Talent Fund (2011A002) and National Key Program of Clinical Science (WBYZ2011-873). The study sponsors had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors G.L., D.F., and X.X.Q. contributed to data analysis and wrote the manuscript. J.L.F., and L.J.L. performed the immunoassay. Y.H.W., L.W.H. and L.X.L. contributed to the data collection. I.C.E. and M.Y. L contributed to interpretation of the data, and revised the manuscript. S.G. and M.L. were responsible for the study design, protocol development, and interpretation of data and revised the manuscript. All authors have approved the final version of the article.
Conflict of interest The authors declare no competing financial interests. All authors have reviewed the contents of the manuscript being submitted, approve of its contents, and validate the accuracy of the data. No part of this material has been published previously nor is being considered for publication elsewhere.
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European Neuropsychopharmacology (2018) 000, 1–11
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Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity Ge Li a,1, Dan Feng b,1, Xiaoxue Qu b, Junling Fu a, Yonghui Wang b, Lianxia Li b, Lujiao Li a, Lanwen Han b, Issy C. Esangbedo c, Mingyao Li d, Ming Li a,2,∗, Shan Gao b,2,∗ a
Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China b Department of Endocrinology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, China c Health Weight Program, The Children’s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, PA 19104, USA d Departments of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA Received 6 January 2017; received in revised form 24 February 2018; accepted 21 May 2018 Available online xxx
KEYWORDS Adipokine; Self-concept; Youths; Obesity
Abstract The mechanisms by which obesity increases the risk of psychosocial disorders remain unclear. We aimed at exploring the association between obesity and self-concept in Chinese youths and the role of adipokines. Data for 559 participants (aged 14–28 years) were analyzed. Self-concept was assessed by utilizing the Self-Description Questionnaire II (SDQ-II). Subjects with obesity had higher leptin, FGF21 and lower adiponectin levels (all p < 0.001). They also had lower SDQII scores especially in the domains of general school, physical abilities, physical appearance and opposite-sex relations (all p < 0.001). Both elevated FGF21 and leptin were correlated with lower scores in math (p < 0.01), physical abilities (p < 0.01), and opposite-sex relations (p < 0.05), meanwhile FGF21 negatively correlated with the scores in general school and hon-
∗ Corresponding
authors. E-mail addresses: [email protected], [email protected] (M. Li), [email protected] (S. Gao). 1These authors share co-first authorship. 2These authors contributed equally to this work. https://doi.org/10.1016/j.euroneuro.2018.05.015 0924-977X/© 2018 Elsevier B.V. and ECNP. All rights reserved.
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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2
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G. Li et al. esty/trustworthiness, and leptin negatively correlated with physical appearance (p < 0.01) but positively with verbal (p < 0.01). In contrast, decreased adiponectin was correlated with poorer physical abilities (p < 0.05), physical appearance (p < 0.05), and parent relations (p < 0.01). Moreover, these associations of leptin, FGF21 and adiponectin with certain domains remained significant after adjustment for BMI and other metabolic confounders. In conclusion, youths with obesity experienced poorly on self-concept, and these associations may be explained in part by adipokines leptin, FGF21 and adiponectin. © 2018 Elsevier B.V. and ECNP. All rights reserved.
1.
Introduction
The increasing worldwide prevalence of obesity in youths is one of the most challenging healthcare problems (Ng et al., 2014). While the physical effects of overweight in youth have been widely documented (Schmidt, 2015), less is known about the psychosocial burden of excess weight, and what is known is largely confined to isolated aspect of psychosocial function such as low self-esteem, depression or body dissatisfaction (Pulgaron, 2013). Moreover, the mechanisms by which obesity increases risk of psychosocial disorder remain unclear (Pulgaron, 2013). It is now widely recognized that adipose tissue is hormonally active, secreting a wide range of peptides known as adipokines, which regulate important physiologic processes in target organs including not only liver, muscle, heart and immune system, but also brain (Fasshauer and Bluher, 2015). In obesity, the adipose tissue dysfunction leads to altered adipokines secretion, therefore contributes towards cardio-metabolic diseases (Bluher and Mantzoros, 2015 and Fasshauer and Bluher, 2015). However, whether adipokines could link available energy stores with psychosocial conditions has rarely been addressed. Self-concept plays an important role in psychosocial assessment. The development of negative beliefs about self can result in maladaptive responses and mental states. The association between obesity and self-concept among youths is still being debated. While some investigations observed that the degree of overweight was significantly associated with evaluation of physical appearance (Danielsen et al., 2012), other studies have not observed a relationship with self-esteem (Young-Hyman et al., 2003). To date, few studies have been conducted to explore multiply domains of self-concept based on large samples in youths with overweight and obesity, and study of the potential mechanisms of obesity on self-concept is still lacking, especially in Chinese population (Chung et al., 2015). Recent studies showed that association between obesity and neurodegenerative diseases could be mediated by the pleiotropic effects of adipokines, particularly by those adipokines which may function through central nervous system (CNS), such as leptin (Dalamaga et al., 2013), adiponectin (Arnoldussen et al., 2014) and FGF21 (Leng et al., 2015). Additionally, Nixon Nixon Andreasson et al. (2010) found that elevated leptin correlated with poor existing self-rated health in men. Based on these recent findings, we therefore hypothesized that the effects of obesity on psychosocial disorders might also be mediated by the dysregulation of those adipokines with established CNS actions. Since the Self-Descriptive
Questionnaire II (SDQ-II) is a leading multidimensional self-concept instrument for adolescents and used widely (Hau et al., 2003 and Marsh, 1990), we aimed to determine the association between obesity and self-concept measured by SDQ-II in Chinese youths based on a large cohort of Beijing Child and Adolescent Metabolic Syndrome Study (BCAMS) (Li et al., 2009 and Wang et al., 2013). Furthermore, we sought to investigate the levels of three adipokines including leptin, adiponectin and FGF21 in obesity, as well as their roles in linking obesity with self-concept.
2. 2.1.
Experimental procedures Participants
Subjects were recruited from the cohort of BCAMS study (Li et al., 2009 and Wang et al., 2013). The BCAMS study evaluated the prevalence of obesity and related metabolic abnormalities including hypertension, hyperglycemia and dyslipidemia in Beijing school-age children (n = 19,593, age 6–18 years, 50% male) from April to October 2004. 4,500 participants were identified as being at high risk due to having one of the followings: overweight defined by body mass index (BMI), elevated cholesterol ≥ 5.2 mmol/l, elevated triglycerides (TG) ≥ 1.7 mmol/l or elevated fasting glucose ≥ 5.6 mmol/l based on finger capillary blood tests. Follow-up study for the BCAMS cohort started in 2012 (Fu et al., 2016). Participants were recruited consecutively through various modalities and underwent medical examination at the healthcare center of Beijing Chaoyang Hospital. Informed consent was obtained from all participants and/or their parents or guardians through all the study processes. The protocol for the follow-up examination was approved by the Ethics Committee at the Beijing Chaoyang Hospital. A total of 559 subjects who completed medical examination and questionnaires were included in the current study.
2.2.
Clinical measurements
Height, weight, and waist circumference (WC) were measured by trained field workers. Participants removed bulky clothing and shoes prior to measurements. Height and WC were measured to the nearest 0.1 cm using a portable stadiometer. WC was measured midway between the lowest rib and the top of the iliac crest. Weight was measured to
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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3 the nearest 0.1 kg using a TANITA Body Composition Analyser (Model TBF-300A, Tanita, Japan). Measurements of right arm systolic and diastolic blood pressure (SBP and DBP) were performed three times, 10 minutes apart and the mean values of the latter two measurements were recorded. BMI was calculated as weight divided by height squared. Subjects with ages below 18 years were classified as overweight, if BMI was between the 85th and 95th percentile, or obesity if BMI was above 95th percentile. Subjects older than 18 years were classified as overweight if BMI ≥ 24 kg/m2 , or obesity if BMI ≥ 28 kg/m2 .
2.3.
Laboratory measurements
A 2 h oral glucose tolerance test (OGTT) using 75 g oral glucose load was performed on each subject in the morning after 10 h of fasting. With the Hitachi 7060 C automatic biochemistry analysis system, blood glucose levels were measured by hexokinase method at fasting and 2 h post-prandial, the concentrations of TG, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were assayed using a standard enzymatic method, and high-density lipoprotein cholesterol (HDL-C) was assessed using precipitate with phosphotungstic acidMg method. High-sensitivity C-reactive protein (hs-CRP) was measured by immunoturbidimetric assay. Insulin, leptin, and adiponectin were measured by sandwich enzymelinked immunosorbent assay, which was developed in the Key Laboratory of Endocrinology, Peking Union Medical College Hospital (Li et al., 1997; 2008 and 2012). FGF21 was measured by Human Quantikine ELISA Kit (R&D Systems, Inc.)(Fu et al., 2016). The intra-assay coefficient of variations (CVs) for insulin, leptin, adiponectin and FGF21 were < 4.1%, < 7.4%, < 5.4%, and < 4.8%, respectively. The inter-assay CVs were < 7.0%, < 9.3%, < 8.5% and < 7.4%, respectively. Insulin resistance was assessed by the homeostasis model assessment (HOMA-IR), calculated as fasting insulin (μIU/ml) × fasting glucose (mmol/l)/22.5 (Matthews et al., 1985).
2.4.
Self-concept
The Chinese version of the SDQ-II questionnaire was used to assess self-concept (Marsh, 1990). SDQ-II was chosen because its development is based on a multi-dimensional theory of self-concept for adolescents, its language and answer format were relatively easy to understand, and it was translated into Chinese and validated for Chinese population (Hau et al., 2003). The SDQ-II consists of 102 questions which comprise 11 multi-item scales: three components of academic self-concept (math, verbal and general school), seven components of non-academic self-concept (physical abilities, physical appearance, parent relations, oppositesex relations, same-sex relations, honesty/trustworthiness and emotional stability), and a global component (general self). Each of the items is a simple declarative statement, the response to which is made on a 6-point scale (1–6 in ascending order of assessment as true).
2.5.
Statistical analyses
Analyses were performed using the Statistical Package for Social Sciences (SPSS 19.0 for Windows, SPSS Inc., USA). Continuous variables were tested for normality using the Kolmogorov-Smirnov test. Non-normal distribution values such as insulin, leptin, adiponectin, FGF21, and HOMA-IR were natural log-transformed (ln) to comply with the normality assumption. Comparisons between groups were conducted using the analysis of variance or general linear model adjusted for age and sex for continuous variables, while categorical variables were analyzed using the Chi-square test. Partial correlation test and multiple linear regression were used to verify possible association between SDQ and obesity indexes, adipokines and metabolic parameters after adjusted for age and gender, and additional covariates when necessary. Level of significance was accepted as p < 0.05 (two sided).
3.
Results
3.1. The general characteristics of the study population The clinical, biochemical features and SDQ scores of the participants stratified by BMI are shown in Table 1. Among the 559 participants, 265 (47.4%) were female. The mean age of all participants was 20.2 years (14–28 years). In this study, 243 (43.5%) had normal weight, 135 (24.1%) were overweight and 181 (32.4%) were obese by their BMI. When comparing to normal weight and overweight peers, obese participants had higher WC, SBP, DBP, TG, LDL-C, HOMAIR, hs-CRP, fasting insulin and lower level of HDL-C (all p < 0.01). As for adipokines, the comparisons of leptin, adiponectin and FGF21 levels in different body weight categories after controlling for age and sex were showed in Fig. 1. As expected, increasing degree of overweight was significantly associated with elevation in leptin and FGF21, but reduction in adiponectin (all p < 0.001). Regarding self-concept, participants with obesity scored lower in general school, physical abilities, physical appearance and opposite-sex relations domains than both normal weight and overweight subjects (all p < 0.001). Additionally, there were marginal significant differences in same-sex relations (p = 0.050) and honesty/trustworthiness (p = 0.059). However, for verbal, parent relations, and emotional stability domains, there were no group differences (p > 0.05). Notably, even in the overweight group, lower scores in the physical appearance (p < 0.01) and opposite-sex relations (p < 0.05) were observed when compared to their normal weight peers, whereas in same-sex relations and general self domains, the significant difference was observed only between the obesity and normal weight groups.
3.2. Relationship between self-concept and adiposity indexes, adipokines and metabolic parameters After adjustment for age and sex, the correlations observed among adiposity indexes, adipokines, metabolic
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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G. Li et al.
Table 1
The characteristics of the study population. Total
Normal
Overweight
N (female %) 559(47.4%) 243(59.7%) 135(44.4%) Age (yrs) 20.2(2.9) 20.2(2.9) 20.2(3.1) BMI (kg/m2 ) 25.7(5.7) 20.6(2.1) 25.9(1.3)∗∗ WC (cm) 85.4(14.6) 73.0(6.9) 86.5(7.0)∗∗ SBP (mmHg) 115(14) 107(12) 115(10)∗∗ DBP (mmHg) 73(10) 68(9) 73(8)∗∗ TG (mmol/L) 1.13(0.83) 0.85(0.41) 1.11(0.70)∗∗ TC (mmol/L) 4.35(0.92) 4.18(0.89) 4.38(0.92) LDL-C (mmol/L) 2.53(0.79) 2.25(0.72) 2.60(0.71)∗∗ HDL-C (mmol/L) 1.44(0.32) 1.57(0.32) 1.41(0.32)∗∗ Fasting glucose (mmol/L) 4.92(0.69) 4.88(0.75) 4.86(0.35) 2h-glucose (mmol/L) 6.06(1.84) 5.94(2.19) 5.85(1.08) HbA1C (%) 5.38(0.48) 5.36(0.49) 5.33(0.29) Fasting insulin (mU/L)& 6.96(2.10) 4.57(1.86) 6.69(1.77) ∗∗ HOMA-IR 2.04(1.92) 1.25(1.34) 1.70(0.95)∗ Hs-CRP (mg/L) 1.81(2.54) 1.02(2.03) 1.80(2.31)∗∗ Self-description questionnaire scores (age- and sex- adjusted mean and s.e.m) Verbal 4.1(1.0) 4.0 (1.0) 4.1 (1.1) Math 3.9(1.2) 4.0 (1.2) 3.8 (1.2) General school 4.4(0.8) 4.5(0.7) 4.5(0.8) Physical abilities 3.8(1.1) 4.0(1.1) 3.9(1.2) Physical appearance 4.1(0.8) 4.4(0.7) 4.1(0.7)∗∗ Opposite-sex relations 4.3(0.8) 4.5(0.8) 4.3(0.9)∗ Same-sex relations 4.9(0.7) 5.0(0.6) 4.9(0.6) Parent relations 4.7(0.8) 4.7(0.8) 4.7(0.7) Honesty/trustworthiness 4.5(0.7) 4.5(0.6) 4.5(0.6) Emotional stability 4.0(0.8) 4.0(0.7) 3.9(0.8) General self 4.7(0.7) 4.7(0.7) 4.7(0.8)
Obesity
p-Value
181(33.1%) 20.1(2.9) 32.4(3.7)∗∗, ## 100.7(10.8)∗∗, ## 124(14)∗∗, ## 80(10)∗∗, ## 1.54(1.12)∗∗, ## 4.55(0.92)∗∗ 2.86(0.80)∗∗, ## 1.27(0.23)∗∗, ## 5.02(0.79) 6.38(1.76)∗, # 5.45(0.57) 12.55(1.78)∗∗, ## 3.36(2.38)∗∗, ## 2.89(2.89)∗∗, ##
<0.001 0.963 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.065 0.018 0.050 <0.001 <0.001 <0.001
4.1 (0.9) 3.8(1.2) 4.2(0.8)∗∗, ## 3.4(1.1)∗∗, ## 3.6(0.8)∗∗, ## 4.1(0.8)∗∗ 4.8(0.6)∗ 4.6(0.8) 4.4(0.6) 4.0(0.8) 4.6(0.7)∗
0.712 0.116 <0.001 <0.001 <0.001 <0.001 0.050 0.305 0.059 0.438 0.019
Data are the means (SD) or n%; Abbreviations: BMI = body mass index; WC = waist circumference; HOMA-IR = insulin resistance index; SBP = systolic blood pressure; DBP = diastolic blood pressure; TG = triglycerides; TC = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = highdensity lipoprotein cholesterol; Hs-CRP = high-sensitivity C-reactive protein; FGF21 = fibroblast growth factor 21. Values in bold are significant at p < 0.05. & Data was antinatural logarithmic transformed when in analyses. ∗ p < 0.05, ∗∗ p < 0.01, compared with normal; # p < 0.05, ## p < 0.01, compared with overweight.
parameters and SDQ scores were shown in Table 2. In this analysis, except for domains in parent relations, honesty/trustworthiness and emotional stability, all the six domains including math, general school, physical abilities, physical appearance, opposite-sex relations and general self were negatively correlated with BMI and WC (all p < 0.05), while verbal was positively correlated with obesity index. In addition, as expected, greater BMI and WC were associated with higher FGF21 and leptin, and lower adiponectin (all p < 0.01). On the other hand, higher FGF21 was significantly correlated with decreased self-concept in math (r = −0.124, p < 0.01), general school (r = −0.111, p < 0.05), physical abilities (r = −0.225, p < 0.01), opposite-sex relations (r = −0.113, p < 0.05) and honesty/trustworthiness (r = −0.093, p < 0.05) domains. Leptin also showed the similar correlation in math (r = −0.138, p < 0.01), physical abilities (r = −0.307, p < 0.01) and opposite-sex relations (r = −0.141, p < 0.01), plus inverse correlation
with physical appearance (r = −0.255, p < 0.01), and positive with verbal (r = 0.183, p < 0.01). Unlike those two adipokines, adiponectin was positively correlated with scores in physical abilities (r = 0.100, p < 0.05), physical appearance (r = 0.117, p < 0.05), and parent relations (r = 0.139, p < 0.01). Notably, further adjustment of BMI attenuated most of these associations; however, FGF21 remained significantly correlated with selfconcept in general school (p < 0.05), physical abilities (p < 0.01) and honesty/trustworthiness (p < 0.05) domains, while leptin remained associated with physical abilities (p < 0.001), and adiponectin remained associated with parent relations (p < 0.05). Additionally, we found several classical cardio-metabolic risk factors were associated with certain domains in self-concept, such as blood pressure, fasting insulin, HOMA-IR, HDL-C and TG. In the emotional stability domain, there was no significant correlation among the variables analyzed in this study.
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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Partial correlation between PSDQ and adiposity index, adipokines and metabolic parameters. BMI
FGF21∗
Adiponectin∗
Leptin∗
SBP
DBP
FBG
FINS∗
TG∗
HDL-C
0.916## / 0.101# −0.141## −0.136## −0.286## −0.324## −0.136## −0.089# −0.028 −0.05 −0.046 −0.113#
0.324## 0.321## 0.055 −0.124## −0.111# −0.225## −0.075 −0.113# −0.044 −0.05 −0.093# −0.03 −0.066
−0.374## −0.356## −0.082 0.044 −0.018 0.100# 0.117# 0.051 0.042 0.139## 0.055 0.041 0.001
0.733## 0.712## 0.183## −0.138## −0.09 −0.307## −0.255## −0.141## −0.055 −0.026 −0.019 −0.028 −0.058
0.529## 0.527## 0.093 −0.101# −0.084∗ −0.146## −0.200## −0.055 −0.073 −0.011 −0.022 −0.009 −0.094
0.482## 0.463## 0.079 −0.182## −0.124## −0.165## −0.114# −0.081 −0.069 0.015 −0.006 0.018 −0.085
0.063 0.074 0.035 −0.109# −0.07 −0.016 0.022 0.006 0.013 0.047 −0.006 0.052 −0.016
0.643## 0.604## 0.190## −0.136## −0.086 −0.238## −0.263## −0.101# −0.085 −0.06 −0.021 −0.045 −0.072
0.293## 0.303## 0.015 −0.081 −0.053 −0.048 −0.097# −0.028 0.028 −0.028 −0.039 0.039 −0.025
−0.337## −0.285## −0.039 0.058 0.049 0.154## 0.128## 0.106# 0.074 0.094# 0.026 0.044 0.118#
/ −0.068 −0.073 −0.059 −0.056 −0.007 0.052 0.024 −0.00001 −0.054 0.027 −0.028
0.076 0.002 −0.079 −0.105# −0.170## 0.024 −0.049 −0.019 −0.041 −0.096# −0.015 −0.059
−0.023 −0.022 −0.028 −0.065 −0.027 0.011 −0.023 −0.023 0.104# 0.043 0.012 −0.034
0.172## 0.081 −0.058 0.002 −0.144## 0.015 0.005 0.052 0.029 −0.017 0.010 0.019
0.108# 0.005 −0.028 −0.019 −0.023 −0.019 0.018 −0.034 −0.023 −0.029 0.036 −0.030
0.056 0.031 −0.127## −0.053 −0.045 0.057 −0.027 −0.035 0.011 0.035 0.022 −0.028
0.029 0.030 −0.089# −0.067 −0.014 0.047 0.020 0.027 0.029 −0.036 0.045 −0.007
0.055 0.115## −0.049 −0.023 −0.105# −0.042 0.018 −0.011 −0.033 −0.036 −0.002 0.0005
0.102# −0.019 −0.022 −0.018 0.001 0.003 0.029 0.050 −0.013 −0.040 0.055 −0.006
0.035 0.032 0.002 −0.010 0.080 0.006 0.019 0.059 0.078 0.002 0.002 0.076
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Age- and sex-adjusted BMI / WC 0.916## Verbal 0.143## Math −0.113# General school −0.108# Physical abilities −0.284## Physical appearance −0.353## Opposite-sex relations −0.175## Same-sex relations −0.114# Parent relations −0.027 Honesty/trustworthiness −0.026 Emotional stability −0.056 General self −0.101# Age-,sex- and BMI- adjusted WC / Verbal / Math / General school / Physical abilities / Physical appearance / Opposite-sex relations / Same-sex relations / Parent relations / Honesty/trustworthiness / Emotional stability / General self /
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Data are the partial correlation coefficient. Abbreviations: BMI = body mass index; WC = waist circumference; SBP = systolic blood pressure; DBP = diastolic blood pressure; TG = triglycerides; HDL-C = high-density lipoprotein cholesterol; FBG = fasting blood glucose; FINS = fasting insulin; FGF21 = fibroblast growth factor 21. Values in bold are significant at p < 0.05. ∗ natural logarithmic transformed when in analyses. # p < 0.05, ## p < 0.01.
5
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
Table 2
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G. Li et al. Fig. 1 FGF21, adiponectin, and leptin levels according to body weight status. Data were shown as means ± s.e.m. FGF21, adiponectin, and leptin levels were natural logtransformed when in analyses. p values were calculated from general linear regression model with post hoc comparisons after controlling for age and gender.
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To further assess the independent role of adipokines in self-concept, a number of regression analyses were conducted by adding all the significantly associated variables (including demography-, adiposity-, and metabolic- variables as shown in Table 2 into the models for each domain. Thus, except for age and gender, Table 3 presents all variables that were entered initially for stepwise regression for those variables that remained significant in the final mode for each domain. As shown in Table 3, after controlling for adiposity and other metabolic confounders, both elevated FGF21 (β = −0.163, p < 0.001) and leptin (β = −0.326, p < 0.001) could independently predict lower physical abilities. In addition, higher FGF21 independently predicted lower general school (β = −0.083, p = 0.004) and honesty/ trustworthiness (β = −0.059, p < 0.05), while increased leptin was associated with decreased math (β = −0.165, p = 0.001), and decreased adiponectin was associated with worse parent relations (β = 0.149, p = 0.004). The important correlations between above-noted adipokines and domains of self-concept were also shown in Fig. 2. These results indicated that increased leptin and FGF21 and decreased adiponectin were the independent mediators of self-concept in some domains.
4.
Discussion
The main finding of the study was that the adolescents and young adults with obesity had lower SDQ-II scores compared to non-obese groups, especially in the general school, physical abilities, physical appearance and opposite-sex relations domains. Adiposity measures, blood pressure, fasting glucose, insulin, TG, HDL-C and three adipokines were correlated with SDQ-II scores. Moreover, the associations between SDQ-II scores and adipokine leptin, FGF21 and adiponcectin were attenuated but remained significant for certain domains after adjusting for BMI, suggesting that these adipokines might be the potential mediators implicated in obesity related self-concept. To the best of our knowledge, this is the first study that provides information about the mediating role of such adipokines in self-concept, especially in Chinese youth. The consequences of obesity are far reaching, not only including health-related physical outcomes, but also psychological, social and behavioral consequences. In agreement with previous studies (Reinehr et al., 2012 and Steinberger et al., 2009), we found that participants with obesity had high blood pressure, high TG, TC, LDL-C, low HDL-C, and adverse profile of adipokines including high leptin, FGF21 and low adiponectin. Since obesity has become a focus for preventative and management action, adolescents’ psychological state has come under increasing attention. Self-concept has been broadly studied since its first theoretical definitions. Self-concept, broadly defined, is a person’s perception of him- or herself. These perceptions are formed through experience with and interpretations of one’s environment. They are influenced especially by evaluations, by significant others, reinforcements, and attributions for one’s own behavior (Shavelson et al., 1976). Currently, there is no universal method to assess the self-concept. SDQ-II is considered a multi-dimensional instrument to assess self-concept for adolescents, which has been validated
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7 Table 3 Stepwise regression analysis for adiposity-, adipokines- and metabolic variables with each selected domain of selfconcept. Domain Math General school Physical abilities Physical appearance Opposite-sex relations Same-sex relations Parent relations Honesty/trustworthiness
Variables ∗
Leptin DBP FGF21∗ Leptin∗ FGF21∗ BMI BMI BMI Adiponectin∗ FGF21∗
β
STD β
t
P
−0.165 −0.025 −0.083 −0.326 −0.163 −0.051 −0.026 −0.010 0.149 −0.059
−0.143 −0.216 −0.123 −0.300 −0.162 −0.365 −0.179 −0.086 0.123 −0.101
−3.313 −3.418 −2.889 −7.180 −3.865 −9.029 −4.176 −1.988 2.860 −2.380
0.001 0.001 0.004 <0.001 <0.001 <0.001 <0.001 0.047 0.004 0.018
Data was adjusting for age, sex, BMI/WC and other related variables according to Table 2. Abbreviations: BMI = body mass index; WC = waist circumference; FGF21 = fibroblast growth factor 21; DBP = diastolic blood pressure. Values in bold are significant at p < 0.05. ∗ natural log-transformed when in analyses. STD β indicates standardized regression coefficient
in Chinese population (Hau et al., 2003). In this study, we observed that compared to normal weight group, obese group had lower SDQ-II scores indicating that they had serious doubts about their self-worth and lacked confidence. Similar to our results, in a study of Hong Kong children, Sung et al. (2005) observed that overweight children perceived themselves to have poorer appearance, sports competence, overall physical self-concept and self-esteem than normal weight children using physical self-descriptive questionnaire. In another study consisting of 263 Cree schoolchildren in Canada, Willows et al. (2013) reported that children with greater adiposity had lower scores for global self-concept, the intellectual and school status and physical appearance domain of self-concept, which was consistent with our results. In addition, our study revealed that overweight and obese participants scored lower in opposite-sex relations, which was consistent with Gibson’s observation in Australian children (Gibson et al., 2008). Taken together, those previous studies and ours revealed that obese youths exhibited poor self-concept among different races, even though the age distribution, sample size or/and measures of psychosocial functioning varied between studies. The underlying mechanisms with these associations are unclear. However, it is known that a number of adipokines, such as leptin, adiponectin and FGF21, interact directly with specific nuclei in certain areas of the brain (Arnoldussen et al., 2014 and Leng et al., 2015). Adipose tissue dysfunction and adipokine secretion dysregulation is frequently found to accompany obesity. This results in dysregulation of not only metabolism, but also neurodegeneration, synaptic plasticity, neurogenesis and memory consolidation (Bluher and Mantzoros, 2015; Dalamaga et al., 2013 and Fasshauer and Bluher, 2015), suggesting those adipokines might be the potential link between excess of obesity and psychosocial conditions. As we predicted, in our study, elevated leptin and FGF21, and decreased adiponectin were found to be associated with the degree of obesity. Further, with the increase in leptin or FGF21 levels and a decrease in adiponectin, SDQ-II scores were significantly decreased in several domains. Notably, the predicting role of FGF21 for general school, physical
abilities and honesty/trustworthiness, and leptin for physical abilities and math, and adiponectin with parent relation remained evident even after adjusting for BMI as well as other obesity-related metabolic parameters. This suggests that those adipokines might play an important role in mediating obesity and self-concept. Leptin is the first discovered adipokine and has an important role in the regulation of appetite, food intake, and energy expenditure, thus known as the “anti-obesity hormone”. However, the levels of leptin generally parallel the amount of adipose tissue present, and obesity is generally associated with elevated circulating levels of leptin, presumably a marker of leptin resistance (Fasshauer and Bluher, 2015). In addition, studies showed that leptin had neuroendocrine function, leptin may act as a ‘‘master switch’’ for the hypothalamic neuroendocrine axes by binding to its receptors located throughout the CNS. This results in regulation of not only metabolism, growth, and reproduction, but also neurodegeneration, synaptic plasticity, neurogenesis and memory consolidation (Dalamaga et al., 2013). A research in Sweden revealed that higher levels of leptin were associated with poor self-rated health in men in crosssectional analysis when controlling for age and BMI (Nixon Andreasson et al., 2010). A study in Japanese men (Otsuka et al., 2006) observed that individuals who perceived higher stress had increased leptin levels, thus leptin resistance of the hypothalamus may be involved in the pathogenesis of this inability of leptin to affect hypothalamic-pituitaryadrenal (HPA) axis activity. As mentioned above, we found that participants who had higher leptin scored lower in four out of six BMI/WC-related domains including math, physical abilities, physical appearance and opposite-sex relations. Moreover, the reverse association of leptin with math and physical abilities domains remained significant when controlling for BMI or WC. These outcomes revealed that the presence of leptin resistance in obesity may contribute to the decreased self-concept. FGF21 is a member of the FGF superfamily that is predominantly produced by the liver and adipose tissue and acts like a hormone that is critical for regulation of glucose and lipid metabolism, and thus a potential novel drug
Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
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Please cite this article as: G. Li et al., Role of adipokines FGF21, leptin and adiponectin in self-concept of youths with obesity, European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.05.015
Fig. 2 Scatter-plot of each selected domain of self-concept and adipokine levels. X-axis represents the adipokine levels and Y- axis represents each selected domain of selfconcept. p value and β for the adipokines in the liner regression model were adjusted for age, sex, body mass index/ waist circumference, and other related variables according to Table 2. FGF21, adiponectin, and leptin levels were natural log-transformed when in analyses. Lines are derived from linear regression models.
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9 target for treating diabetes (Fasshauer and Bluher, 2015 and Gaich et al., 2013). Notably, like leptin, FGF21 can cross the blood-brain barrier (Hsuchou et al., 2007 and Tan et al., 2011) and thereby act in the CNS to induce sympathetic nerve activity, energy expenditure and weight loss (Owen et al., 2014), and enhance hepatic gluconeogenesis through activation of the HPA (Bookout et al., 2013 and Potthoff and Finck, 2014). However, as demonstrated by our study, plasma concentrations of FGF21 were found to be elevated in individuals with obesity (Dushay et al., 2010 and Fasshauer and Bluher, 2015), suggesting the existence of a postulated FGF21-resistant state in humans. Interestingly, our study also showed that elevated FGF21 was correlated with decreased levels of obesity-related self-concept, especially in general school and physical abilities domains, and these associations remained significant even after adjusted for BMI and other related metabolic factors. Similar to leptin, this also suggests that the presence of resistance in CNS or compensatory response might contribute to obesity-related decrease of academic and non-academic self-concept. Therefore, improving the leptin and FGF21 resistance in obese youths can not only benefit their metabolic outcomes but also has the potential to improve their psychological, social and behavioral consequence. Given that the CNS is likely a significant target for the potential benefits of FGF-21 in the treatment of diabetes and obesity (Leng et al., 2015), there is a great deal of value to investigate its treatment function in psychological disorders. Adiponectin is almost exclusively produced by adipocytes. In addition to beneficial peripheral effects on insulin sensitivity, anti-inflammatory, and antiapoptotic properties, it also acts in the brain to increase energy expenditure and may promote weight loss (Fasshauer and Bluher, 2015). Unlike leptin and FGF21, circulating adiponectin levels were decreased in multiple metabolic disorders including obesity and related diseases (Bluher and Mantzoros, 2015). In this study, we also found that adiponectin was inversely related to obesity, and its decreased levels were associated with lower self-concept, especially in physical abilities and appearances, and parent relations. Since decreased adiponectin serum concentrations have been found to be associated with mild cognitive impairment and Alzheimer’s disease (Teixeira et al., 2013), thus it might be that the adjustment function of CNS also contributes to its connection with obesity-related self-concept. Strengths of our study include the well-characterized cohort and the novel finding that obesity related self-concept may be partially mediated by adipokines: leptin, FGF21 and adiponectin. Our study also has methodological limitations. First, the sample size is relatively small, which, however, provided more than 80% power to detect significant associations at the r = 0.20 at the conventional p < 0.05 level. Second, the questionnaire of SDQ-II is suitable for adolescents, but youth adults were also included in our study, although similar results were found when analyses were stratified by adolescents and youth adults. Third, the participants are at risk for metabolic syndrome and the frequency of metabolic disorders could be higher than the general population, thus our finding may not be simply generalized to other populations. Future studies with larger sample sizes and validating in various populations will be needed.
In conclusion, we found that youths with obesity in this Chinese population experienced poorly on self-concept, and it might be partially mediated by adipokines: leptin, adiponectin and FGF21. Since increased leptin and FGF21, and decreased adiponectin levels were found to be involved in this process, our results suggest that intervention by improving the sensitivity of leptin and FGF21, and increasing the levels of adiponectin in these youths might benefit not only the metabolic outcomes, but also the psychological, social and behavioral consequences. Future work should focus on applying longitudinal and experimental designs to assess causality.
Acknowledgments We gratefully thank all the participants in the “Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study”.
Role of the funding source This work was supported by key program of Beijing Municipal Science &Technology Commission (D111100000611001); National Key Research program of China (2016YFC1304800); Beijing Science & Technology Star Program (2004A027); Novo Nordisk Union Diabetes Research Talent Fund (2011A002) and National Key Program of Clinical Science (WBYZ2011-873). The study sponsors had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors G.L., D.F., and X.X.Q. contributed to data analysis and wrote the manuscript. J.L.F., and L.J.L. performed the immunoassay. Y.H.W., L.W.H. and L.X.L. contributed to the data collection. I.C.E. and M.Y. L contributed to interpretation of the data, and revised the manuscript. S.G. and M.L. were responsible for the study design, protocol development, and interpretation of data and revised the manuscript. All authors have approved the final version of the article.
Conflict of interest The authors declare no competing financial interests. All authors have reviewed the contents of the manuscript being submitted, approve of its contents, and validate the accuracy of the data. No part of this material has been published previously nor is being considered for publication elsewhere.
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