Exploration Of Childhood Obesity-related Genes, Adipokines Profiles, And Metabolic Phenotypes

[Background]The alarming increase in prevalence of childhood obesity and its related cardio-metabolic disorders such as metabolic syndrome(MS),type 2 diabetes mellitus(T2DM),cardiovascular disease(CVD),and cancer have become a global health problem.Additionally,the childhood obesity and metabolic disorder are more likely to continuous to adulthood.Obesity is influenced by genetic and environmental factors.To date,genome-wide association studies(GWAS)have identified numerical loci(such as FTO)that contribute to obesity.However,the majority of these studies were conducted in populations of European ancestry whereas studies of pediatric obesity in Asians remain limitedRecent studies demonstrate that not all obese individuals have metabolic complications.A unique subset of obese,known as 'metabolically healthy but obese'(MHO),display favorable metabolic profiles.So far,there are still no effective method to discriminate between MHO and metabolically unhealthy obese(MUO)phenotypes.Searching new biomarker to discriminate the two subset of obese may play an important role in the early intervention of metabolic abnormalities in teenagers.Adipose tissue is now recognized as an important endocrine organ that secretes a variety of bioactive proteins collectively called adipokines,which can greatly influence metabolic effects,and dysregulation of adipokines in obesity leads to insulin resistance,systemic inflammation and abnormal cardiovascular function,particularly by the adipokines which may function via the central nervous system(CNS),such as leptin,adiponectin,resistin,fibroblast growth factor 21(FGF21)and retinol binding protein 4(RBP4).Betatrophin,a noval adipokine,is also named as Lipasin,is a nutritionally-regulated secreted protein.Rescent study have found that the obese people will appear adipokine abnormity before the metabolic disorder.Therefore,detecting the adipokines as early predictors of the metabolic unhealthy phenotype among obese subjects is really important to make the target treatment plan.We therefore investigate the association between the adipokines,obesity-related loci and metabolic phynotypes in Chinese children and adolescents recruited from the cohort of Beijing Children and Adolescents Metabolic Syndrome(BCAMS)study.[Objective](1)To assess the influence of adult obesity-related loci on obesity and metabolic disorder among children aged 6-18 in Beijing.(2)To analyze whether dysregulation of adipokines secretion could discriminate between MHO and MUO phenotypes in Chinese Children.(3)To assess the association between circulating betatrophin and glucose homeostasis as well as other cardiometabolic variables in a cohort of youths at risk for metabolic syndrome[Methods]We conducted a cross-sectional study consisted of 3506 children aged 6-18 years old from Beijing children and adolescents metabolic syndrome study(BCAMS)in 2004.We conducted follow up study after 10 years of BCAMS investigation.A total of 559 subjects were recruited in a center at Beijing Chaoyang Hospital.Metabolic Syndrom(MS)was diagnosed using a modified Adult Treatment Panel ?(ATP ?).Homeostasis model of assessment insulin resistance(HOMA-IR)was used to access insulin resistance(IR).MHO was defined strictly by absence of any classical components of metabolic syndrome(MS)and insulin resistance(IR).Physical activity and dietary information were collected by questionnaire.Single nucleotide polymorphisms(SNPs)were genetyped by mass-spectrography.Serum adipokines and insulin were measured by enzyme-linked immunosorbent assay(ELISA).Serum 25-hydroxyvitamin D(250HD)levels were measured by electro-chemiluminescence immunoassay.Comparisons were made among groups using t test or analysis of variance(ANOVA)or chi-square test.Multivariate logistic regression analysis and multiple linear regression analysis were performed to multivariate analysis.[Results](1)The influence of adult obesity-related SNPs on pediatric obesity and metabolic characters?The relationships between adult obesity-related SNPs and childhood obesity and adipokinesAfter correction for multiple comparisons,six SNPs were robustly associated with obesity:MC4R-rs2331841(P = 2.8×10-7),FTO-rs1558902(P = 5.6 ×10-5),GNPDA2-rs16858082(P = 3.4 ×10-4),PCSK1-rs261967(P = 0.001),SEC16B-rs516636(P = 0.004)and MAP2K5-rs4776970(P = 0.004),with odds ratio from 1.211 to 1.421;while ITIH4-rs2535633 and BDNF-rs2030323 showed nominal association with obesity(P<0.05).Similar trend was also evident in relation to obesity-related anthropometric traits i.e.body mass index(BMI),waist circumference,percent body fat and upper arm circumference.Moreover,the risk alleles of six SNPs,FTO-rs 1558902(P = 0.002),MC4R-rs2331841(P = 0.003),MAP2K5-rs4776970(P = 0.003),GNPDA2-rs16858082(P = 0.007),PCSK1-rs261967(P = 0.009)and BDNF-rs2030323(P = 0.027)displayed significant(P<0.004)or nominal association with leptin levels,respectively,and their cumulated genetic scores showed stronger association with increasing leptin levels(P =6.2×10-11).?The relationships between adult obesity-related SNPs and childhood metabolic charactersThe above obesity-related SNPs also correlated with childhood metabolic phenotypes.When further adjusted for BMI,the risk alleles of KCNQ1-rs2237892 remained significantly associated with decreasing HDL-C(P = 3.7×10-4),and MC4R-rs2331841 remained correlated with increasing fasting glucose(P=0.012).(2)The adipokine profiles of metabolically healthy and unhealthy obese childrenMHO was defined by combined CR and IR.The prevalence of MHO was 20.4%.After adjustment for potential confounders,including pubertal stage and BMI,MHO had more favorable plasma adipokine profiles than MUO:higher adiponectin(P = 0.002),and lower leptin(P<0.001),RBP-4(P=0.001),and SPARC(P = 0.011)concentrations.Compared to NWH,MHO displayed increased leptin,resistin and RBP-4,and reduced adiponectin concentrations(all P<0.05),but similar in FGF21 and SPARC levels.Among obese individuals,multivariate logistic analyses showed that decreased levels of SPARC(OR = 0.821 per SD,95 CI= 0.695-0.971,P=0.021),RBP-4(OR = 0.772,95%CI=0.644-0.926,P = 0.005),and leptin/adiponectin(OR = 0.576,95%CI = 0.433-0.765,P<0.001)were remained independent predictors of MHO.In addition,compared with those who had no above-mentioned adipokine abnormality,children with 3 adipokine abnormalities had significantly reduced odds to be MHO(OR = 0.201,95%CI=0.097-0.415),whereas,had increased odds of being MS(OR = 2.880,95%CI =1.584-5.237).(3)The association between circulating betatrophin and glucose homeostasis as well as other cardiometabolic variables in a cohort of youth at risk for metabolic syndromeParticipants in the highest quartile of betatrophin levels had the highest levels of total cholesterol(P<0.001),triglyceride(P<0.001)and low-density lipoprotein cholesterol(P<0.001)and the lowest levels of vitamin D(P= 0.003).After stratification by vitamin D status,betatrophin in subjects with vitamin D deficiency were positively correlated with unfavorable metabolic profiles including high blood pressures,dyslipidemia and hyperglycemia,whereas betatrophin in those with higher vitamin D levels only showed negative association with fasting insulin,2h-insulin,and insulin resistance.[Conclusions](1)Several obesity-related loci reported from recent Meta-analysis of genome-wide association studies in adult of East Asian-ancestry populations correlated with Chinese pediatric obesity and metabolic characters.These childhood obesity-related genes highly expressed in central nervous systerm and displayed significant association with leptin levels,indicating that the hypothalamic "leptin resistance" may play a role in the mechanism between genetic factors and obesity.(2)Approximate one-fifth of Chinese obese children can be classified as MHO which was defined by combined CR and IR criteria.Adipokine profiles may be used as a new biomarker to discriminate between MHO and MUO phenotypes in children.In addition,compared with those who had no above-mentioned adipokine abnormality,children with 3 adipokine abnormalities had 80%reduced odds to be MHO,whereas,had three times increased odds of being MS.(3)Elevated betatrophin levels were associated with cardiometabolic risk factors in this young population,but the association was largely dependent on vitamin D status.