A Comprehensive Model of Childhood Adiposity: Examining Brain Structure, Genetics, Cognition, and Environmental Factors in the ABCD Study

The causes for obesity are multifactorial, but much research suggests that heritability plays a large role in intergenerational transmission (Locke et al. 2015; Yengo, Sidorenko, Kemper, Zheng, Wood, Weedon, Frayling, Hirschhorn, Yang, Visscher, et al. 2018). Much of the genes contributing to high body mass index (BMI) are expressed in the central nervous system (Locke et al. 2015; Yengo, Sidorenko, Kemper, Zheng, Wood, Weedon, Frayling, Hirschhorn, Yang, Visscher, et al. 2018). Through this lens, obesity risk may be caused by alterations in the brain, where structural and other downstream functional changes may play a role in appetite dysregulation and cause excess weight gain and maintenance (Morys et al. 2023; Adise, Ottino-Gonzalez, et al. 2023; Adise et al. 2025). Specifically, obesity is associated with changes in brain regions involved in executive functions, impulsivity or decision making, which may help explain why some individuals are more vulnerable to the modern food environment (Morys et al. 2023; García-García et al. 2022; Vainik et al. 2018, 2019; Lowe et al. 2019). Conversely, weight gain itself may further alter brain structure and function: while in mid-life, chronic obesity and associated metabolic changes lead to structural brain damage and cognitive decline, similar associations are observed in children (Adise et al. 2025; Morys et al. 2021; Lowe et al. 2020). Finally, many environmental factors that also interact with brain health (e.g., dietary intake, sleep, physical activity, neighbourhood, household income, or education (Nicolaidis 2019) contribute to the progression and maintenance of obesity (Kweon et al. 2022; Rapuano et al. 2020; García‐García et al. 2019; Barcellos et al. 2018). Understanding the plausible causal mechanisms for obesity development and maintenance in children is imperative, particularly given that excess weight in childhood predicts obesity in adulthood (Simmonds et al. 2016). Prevention and intervention strategies should therefore, at least in part, focus on tackling obesity at a young age. To this end, the relationship between factors contributing to childhood obesity must be disentangled. Currently, studies have been of a correlational nature, limiting the insight into the mechanisms driving excess weight. While a few studies provide evidence for a directional relationship between genetic or environmental factors (e.g., cognition, diet, brain structure, or socioeconomic status (Kim and Colabianchi 2022; Rapuano et al. 2020; Emmett and Jones 2015; Adise, Ottino-Gonzalez, et al. 2023; Adise, Boutelle, et al. 2023) with weight gain, no studies have evaluated the factors in combination. Omitting simultaneous influences of different factors on childhood obesity might lead to biased effect estimates, most often inflating the apparent effect of the included factors. One way to alleviate this concern is to create a model including multiple variables that might contribute to obesity. This has become possible with the advent of population-based brain imaging datasets providing large sample sizes. Here, using a large-scale brain dataset of the Adolescent Brain Cognitive Development (ABCD) study, we will examine the longitudinal associations between multiple obesogenic factors and weight gain while disentangling environmental factors that can lead to childhood obesity directly but also via the brain. Based on the previous literature, we will also use cognitive and impulsivity measures to investigate whether they mediate the relationship between the brain and obesity. This will help answer the question of the exact relationship between obesity measures and potential factors that influence obesity and weight gain. Overall, this study aims to develop and test a comprehensive model of weight gain in children by simultaneously evaluating the longitudinal influences of genetic, neural, cognitive, and environmental factors. This is a largely exploratory study in which the primary associations of interest are how brain structure interacts with weight change in children and what factors can modify this relationship.