The Structural And Functional Basis Of Body Mass Index And Its Influencing Factors

Over the past four decades,the prevalence of obesity has been rising steadily in the whole world.According to estimates by the World Health Organization,more than 1.9 billion adults are overweight worldwide,of which 600 million are obese.In addition,China’s obese population ranks first around the world.Obesity becomes a major public health problem and a major risk factor for global death,and it is associated with increased risk and morbidity for type II diabetes,cardiovascular disease,certain cancers and neurodegenerative diseases,and results in at least 2.8 million deaths per year.In the past few decades,although researchers have made many efforts to understand the underlying pathophysiological mechanisms of overweight and obesity,the underlying mechanisms behind body mass index(BMI)is not fully understood.A better understanding of the brain-related mechanisms of BMI and its association with genetic risk and eating behavior not only helps explain obesity-related cognitive and behavioral disorders,but may also help develop rational,tailor-made interventions to prevent or reverse weight gain.The prevalence of obesity in modern society mingt be attibuted to complex interactions between multiple genetic,behavioral,and environmental factors.At the neurological level,brain structure and function may play an important role in the pathophysiological processes of overweight and obesity,especially those involving energy metabolism,reward processes,and executive control.At the genetic level,studies have shown that 40% to 70% of the variation of obesity is due to a genetic variation,and multiple genome-wide association studies and meta-analyses have identified more than 250 BMI-related loci.However,although body size and composition are largely genetically determined,genetic factors alone do not explain the rapid increase in obesity rates.Weight gain and obesity stem from a long-term imbalance between energy intake and energy expenditure.Obesogenic environment factors(such as Western-style snacks,high-sugar drinks,and sedentary lifestyle)are undoubtedly a challenge to maintain weight.In a modern environment with lower food prices and more food consumption,the effect of eating behavior on body weight cannot be ignored.Besides,studies have shown that eating behavior is linked to genetic basis and may interact with genetic susceptibility of obesity,that is,poor eating behavior may amplify the effect of genes on obesity.In summary,obesity is related to complex interactions between genetic,behavioral,and environmental factors,but inconsistencies in existing research have hampered our understanding of the relationship between weight disorders,brain,genetic and behavioral factors.Therefore,this study aims to understand the structure and function basis of BMI,and to understand how the genetic susceptibility of obesity and eating behavior affect BMI from the perspective of genetic and environmental factors,and to understand the underlying mechanism of BMI by examine the interaction among genetic factors,brain,eating behavior and BMI.The purpose of Study 1 was to explore the associations between BMI and the brain based on structural and functional neuroimaging data.Considering the differences and inconsistencies between existing findings,we combined a cortical-based structural index and resting-state functional connectivity(FC)to examine associations between BMI and brain in a sample of more than 700 participants.The results were cross-validated using bioelectrical impedance-based BFP.Analysis of whole-brain cortical thickness revealed that the bilateral superior frontal gyri(SFG),left inferior frontal gyrus(IFG),and right medial orbitofrontal cortex(mOFC)were negatively correlated with BMI.Results of BFP verified roles of the left SFG and right mOFC.Besides,the volume in right amygdala was significantly positively correlated with BMI and BFP.Analysis of resting-state FC suggested that higher BMI was associated with weaker FC between many regions,especially those involving the right SFG,insula,inferior temporal gyrus and parietal lobe,might play important roles in regulating BMI.These differences in brain structure and FC may reflect dificits in cognitive and reward functions which are associated with higher BMI.Study 2 aims to investigate how genetic factors affect body mass index,and explore the mediating role of the brain and the moderating role of the genetic basis.Based on a previous genome-wide association study,we calculated polygenic risk scores(PGS)and explored the interpretation rates of PGS on BMI and BFP through regression analysis.Then,based on the results in study 1,we extracted the brain structure and FC related to BMI and explored the correlation of PGS and brain indexes.Finally,in order to figure out the relationship between PGS,brain and BMI,we performed mediating effect and moderating effect annalyses.We found that PGS can significantly predict present BMI and BFP and might be associated with brain structure and FC.More importantly,FC between the left amygdala and the right precuneus may mediate the effect of PGS on BMI and BFP.We think that polygenic risk score might be associated with reduced information exchange between the precuneus and amygdala in individuals at high risk of obesity,which may lead to the imbalance between individual cognitive control and reward processes,which in turn leads to the increase in body mass index.Study 3 aims to explore the neural mechanisms by which eating behavior affects BMI and the interaction between diet behavior and genetic factors.We measured eating behavior by the Dutch Eating Behavior Questionnaire and found that restrained eating was related to BMI and BFP.Subsequently,based on the results of Study 1,we examined the relationship between restrained eating and BMI-related brain structure and FC.Results showed that restrained eating was associated with the right SFG and mOFC and FC between the left inferior parietal lobe(IPL)and right IFG.Then,we established a structural equation model and found that restrained eating played a partial mediation role between the right SFG and BMI and the FC between left IPL and right IFG and BMI,and such result was repeatable on BFP.In addition,combined with the results in Study 2,we examined the multiple mediating effects of restrained eating and FC between PGS and BMI,and tested whether there was an interaction among restrained eating and brain or PGS.We found that the FC between the left amygdala and the right precuneus and restrained eating had a significant mediating effect in the relationship between PGS and BMI,but the interaction between the PGS and restrained eating was not significant.Similar results were found in the analysis of BFP.Combining the results of the three parts,it can be found that BMI was related to structure or FC of the SFG,mOFC,insula,amygdala and parietal lobe;genetic architecture might affecte BMI and BFP through brain structure and function,especially the FC between left amygdala and right precuneus;estrained eating might play a partial mediating role between right mOFC and FC between left amygdala and right precuneus and BMI;restrictive eating behavior and genetic basis may influence BMI by acting on the brain,thereby affecting BMI and BFP.In summary,this study explored the underlying mechanisms of BMI on the three levels of neurology,heredity and behavior.The results can provide a better understanding of the behavioral and biological mechanisms involved in obesity and provide theoretical guidance for the development of effective intervention strategies for obesity.