Associations of GLP-1-related genotypes with appetitive traits, food cue reactivity, and prospective weight gain in pre-adolescence

Project Summary Obesity is a chronic disease that is increasingly common, resistant to treatment, and responsible for a broad range of medical comorbidities and excess mortality. Pediatric obesity is especially concerning as it frequently persists throughout life. The causes of obesity involve interactions of genetics and environmental

factors. The Behavioral Susceptibility Theory suggests genetic factors predispose individuals to unfavorable appetite regulation such that when they are exposed to highly palatable foods, excess consumption, positive energy imbalance, and weight gain result. Considering obesity polygenic risk scores (PRS) from recent

genome-wide association studies, my previous research found obesity PRSs relate to appetitive traits and BMI in children. As a target of recent effective anti-obesity medications, GLP-1 and associated pathways play an important therapeutic role through appetite regulation. However, there is a knowledge gap as to how the

endogenous GLP-1 pathway may drive or prevent obesity, specifically how genetic variants associated with this pathway may relate to phenotypes of appetitive traits (observable behaviors) and food cue reactivity (a conditioned reward response to food cues). Specific Aim 1 will incorporate genotype and appetitive trait data

collected on a sample of 312 children aged 9-12-years, allowing the association of GLP-1 related genetic variants and appetitive traits to be assessed, both as main effects and in higher order epistatic interactions. This will allow my novel training in methods for high dimensional genetic data analysis. Specific Aim 2 will

leverage fMRI data conducted in a subset of 176 of these children to associate these variants independently and interactively with food cue reactivity in reward regions of the brain. This will allow my novel training in the processing and analysis of fMRI data. Finally, linking these characteristics to deleterious weight gain in pre-

adolescence, Specific Aim 3 will associate GLP-1 related genetic variants independently and interactively with prospective weight gain in these children. It will further explore how appetitive traits and food cue reactivity may mediate an association between GLP-1 pathway heterogeneity and prospective weight gain. This will allow my

novel training in methods for statistical mediation analysis. I will gain further training in the clinical application of obesity research, and professional skills in preparation for an independent career as a physician scientist. This F30 proposal will allow me to contribute to the understanding of causes of obesity through appetitive

mechanisms and this increased etiologic understanding may enhance obesity prevention and treatment efforts. The highly collaborative environment at Dartmouth College, Dartmouth Health, and the Quantitative Biomedical Sciences graduate program will help me to achieve my proposed research and training goals.