| BackgroundThe rising pandemic of pediatric obesity is likely to lower the average age of onset of metabolic disorders including diabetes and metabolic syndrome(MS)and increase their incidence,which has led to substantial social and economic burden worldwide.However,there is a subset of the population of individuals with obesity that are metabolically healthy,and are called metabolically healthy obesity.Metabolic abnormalities were also observed in some normal-weight individuals;these individuals are said to have metabolically obese normal weight(MONW).Importantly,the prevention and detection of metabolic abnormalities are largely unnoticed in normal-weight individuals until the onset of metabolic disorders.Not all individuals with obesity need treatment for metabolic disorders.Accurate classifications and mechanistic understandings for metabolic health among individuals with normal weight and overweight/obesity are essential to developing future precise clinical interventions for metabolic disorders in different individuals and help allocate limited clinical resources.Adipose tissue exhibits vital biologic functions like storing energy and secreting adipokines and regulates metabolic health through different mechanisms.Both genetic and environmental factors are known to contribute to the function of adipose tissues and the development of metabolic disorders.Therefore,in the view of adipose tissue function,we aimed to detect the early biomarkers and therapeutic targets for metabolic disorders among children with normal weight and overweight/obesity.MethodsAbout 3,500 Chinese children aged 6-18 at baseline were included from the Beijing Children and Adolescent s Metabolic Syndrome(BCAMS)study cohort in 2004.In 2015,559 of individuals from the BCAMS cohort completed an in-depth follow-up examination.Lifestyle factors,including diets,physical activities,and sleep duration,were accessed through questionnaires.Birthweight and socioeconomic factors were recorded.Clinical examinations,including puberty evaluation and physical examinations,were completed.Biochemical measurements and adipokine levels were detected.Additionally,fifteen genetic variants associated with Body Mass Index(BMI),five genetic variants related to glucose metabolism,six adiponectin-related genetic variants resulting from Genome-Wide Association Studies(GWAS)in East Asians were assessed.DNA methylation in peripheral blood was detected by 850k chip.Obesity was defined by the standard recommended by the Working Group on Obesity in China.The presence of MS was defined by the modified criteria of Adult Treatment Panel III(ATP Ⅲ).Being metabolically unhealthy was defined by exhibiting any MS component.Results1.The associations between adipokines and metabolic disordersIn the cross-section analysis among 3,213 children at baseline,the high leptin levels and high Retinol-Binding Protein 4(RBP4)levels can differentiate metabolically unhealthy phenotypes among obese and nonobese individuals.In addition,reduced adiponectin levels,elevated leptin and RBP4 levels were associated with the risk of childhood MS independence of obesity.As the numbers of leptin,adiponectin and RBP4 abnormalities increased,the risks of MS increased accordingly,suggesting that adipokine imbalance might be an early marker for metabolic disorders.In the longitude analysis at 10-year follow-up,childhood RBP4 levels predicted the subsequent development of MS and its components independent of conventional cardiometabolic risk factors.However,the longitude associations of childhood adiponectin and leptin levels with MS were not significant after the adjustment of baseline cardiometabolic risk factors.Combing childhood RBP4 and conventional cardiometabolic risk factors significantly improved the prediction of MS.2.The interactions between adipose function relevant genetic variances and early development environment on metabolic disordersUnfavorable lifestyle,socioeconomic factors,and low birth weight were independent risk factors for the MONW phenotype.The adipose function relevant genetic variances CDKAL1 rs2206734 represents a potential locus for the MONW phenotype.In addition,the protective effects of the CDKAL1 rs2206734 locus could be strengthened by a favorable intrauterine nutritional environment and could be further amplified by favorable childhood environments.Furthermore,the methylation in the promoter region and body CDKAL1 gene was associated with metabolic disorders in normal-weight children with low birth weight,suggesting that methylation might be the link of the interaction between CDK ALI locus and intrauterine nutritional environment.Among the normal-weight children,ADIPOQ rs6773957 locus was correlated with metabolic risks independent of lifestyle factors,but these associations were less evident in the overweight/obese group.A significant interaction between rs6773957 locus and dietary patterns for metabolic health was observed in normal-weight children.The unfavorable dietary patterns could strengthen the metabolic risks conferred by rs6773957 locus.ConclusionsAdipokines leptin,adiponectin and RBP4 reflect the function of adipose tissues,and may be the early biomarkers and potential therapeutic targets for obesity relevant diseases.The adipose function relevant genetic variances CDKAL1 rs2206734,ADIPOQ rs6773957,and CDH13 rs4783244 may be key susceptibility loci contributing to cardiometabolic conditions.The intrauterine nutritional and postnatal environments could modify the metabolic risks conferred by these loci.Personalized nutritional and lifestyle interventions for individuals with specific genetic backgrounds may be recommended as an early possible therapeutic measure to improve metabolic health.Our study gives a new insight into potential strategies to reduce the risk of cardio-metabolic diseases. |
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