Exploration Of Obesity Risk Factors: Role Of Brain Structure And FTO Gene

Obesity and overweight rate rises rapidly.At present,there are no effective measures to stop this trend.So finding the risk factors for obesity is the key to adopting selective interventions or understanding the mechanism of obesity.Obesity is a very complex systemic problem that requires the joint efforts of multiple disciplines.The individual has a complex homeostatic system that regulates energy balance.But why has the obesity problem suddenly swept across the globe in the past half century? A long-term psychological study on obesity found that the most stable behavior difference between obese and normal weight is that the degree of food delicacy has a greater impact on the amount of food consumed by obese people than on normal weight.In an affluent society,the living environment is full of food cues,so excessive food-induced overfeeding is the culprit in the obesity epidemic.What mechanism makes obese people more vulnerable to the temptation of food?Functional magnetic resonance imaging(MRI)studies have shown that excessive rewards for food cues by the reward system or insufficient response to food cues by inhibition control systems may increase the risk of future weight gain.These studies may imply that food cues provoked more rewards expectations and behavioral impulses for those at risk of obesity.In the study of real eating behavior,there are different results about the response of the reward system.The different patterns may be related to genetic factors.Few risk factors for obesity are currently analyzed from the perspective of brain structure.Due to different task paradigms or experimental materials,it is sometimes difficult to compare different functional MRI studies.Because height and weight are basic information,most studies will collect the body mass index(BMI)of participants when collecting nuclear magnetic data.So structural MRI studies on obesity have advantage in data accumulation than functional studies.Looking at the risk factors of obesity from the perspective of brain structure may be able to obtain some potential mechanisms that have not been found in functional MRI studies.With the development of biology,great progress has also been made in the study of the genetic factors of obesity.So far,according to the genetic characteristics and phenotypic characteristics,obesity is divided into three categories.The former two groups have a very small proportion.They are monogenic obesity with other genetic defects and monogenic obesity without other genetic defects.The third type is the most common type: polygenic obesity.Genome-wide association analysis(GWAS)has identified hundreds of genetic markers associated with polygenic obesity,but little is known about the biological mechanisms that link these genetic markers to obesity.The single nucleotide polymorphisms(SNPs)in the first intron of FTO(Fat Mass and Obesity associated)gene is the earliest discovered obesity risk markers,and rs9939609 is a representative one.The current study is unclear about this genetic marker and the biological mechanism associated with obesity.The FTO gene is expressed in many tissues throughout the body,and is particularly expressed in the brain.Studies have found that the polymorphisms of the FTO gene are related to changes in brain structure in some regions,but the results of these studies have not been consistent.There are also studies that have found that polymorphisms in the FTO gene are associated with food intake,especially the eating of high-calorie foods.Therefore,the FTO gene may increase the risk of obesity by affecting the brain structures and functions involved in eating.To look for the brain's structural risk factors for weight change and the possible effects of the FTO gene on this relationship.We conducted the following two studies.Study 1 was a cross-sectional study,participants of 653 high-quality T1 image MRI data and BMI data were collected,and 390 of them completed blood sample collection and DNA sequencing.Three analyses were performed.The first one was a whole-brain regression analysis(Voxel-Based Morphometry VBM analysis)of BMI to brain gray matter volume,and the second was the VBM analysis of brain gray matter comparison between FTO AA/AT carriers and TT carriers;the third analysis is an analysis of the interaction of BMI and FTO genes on gray matter.Study 2 is a longitudinal study,participants who completed the MRI scan and BMI measurement were invited to the laboratory to measure their BMI again after 6 months(time span was 0.5-1 years,266 subjects were obtained).In the longitudinal study,the first analysis compared the differences in grey matter volume between the different categories of BMI changes(increase,decrease,and stability)(brain image data at the first time point);the second analysis compared differences in the frequency of obesity risk alleles(AA/AT,TT)between the different classifications(increased,reduced,and stable);the third one analyzed the interaction of BMI changing categories and FTO gene on gray matter volume.The study 1 found that: a lot of regional gray matter volume was negatively correlated with BMI,including the orbitofrontal,anterior cingulate,insula,dorsal striatum,while the postcentral gyrus and cerebellum was positively correlation with BMI;There was no main effect of FTO gene on gray matter volume;there was a significant interaction between FTO and BMI in the right postcentral gyrus,in which the risk sequence carriers'(AA/AT)BMI was positively correlated with the postcentral gyrus,and this correlation was disappear for the non-carriers(TT).Study 2 found that: BMI increased group and reduced group had more gray matter volume in the left postcentral gyrus compared to BMI stable group.At the cluster level correction(p < 0.001,Monte Carlo simulation),BMI-reduced group had greater gray matter volume in the left middle temporal gyrus than the increase group.FTO gene polymorphisms could not predict the state of BMI changes.At the cluster level correction,the AA/AT carrying group had multiple regions of gray matter volume correlate with BMI changed state,but there was no such relationship in the TT carrying group;there was a significant difference between the BMI reduced group and the stable group in the right insula,the left postcentral gyrus,and the right supplementary motor area.In summary,the study found that:(1)In the early adulthood,subjects had a decrease in gray matter in multiple brain regions related to reward and motivation with increasing BMI at a lower BMI level;but these negatively correlated brains regions cannot predict longitudinal weight gain.(2)A region where the gray matter volume was positively related to BMI including : the left central posterior gyrus(oral representation area,the physical characteristics of foods represented by the central posterior gyrus is an important property of food)can predict future weight changes,so the central posterior changes in regional gray matter volume may be a risk factor for BMI changes.(3)There was no significant difference in BMI or BMI change betweenthe AA/AT carriers and the TT carriers in the FTO gene,which may due to the small sample size;there was no significant difference in gray matter volume between the two groups.(4)Transverse studies showed that the BMI of the FTO gene AA/AT carrier was positively correlated with the volume of the left postcentral gyrus,but not with the TT carrier;longitudinal studies showed gray matter volume of AA/AT carriers but not TT carriers in several brain regions was correlate with BMI change;therefore,the gray matter of the FTO obesity risk allele carriers may be more sensitive to BMI change.