Molecular mediators of the association between child obesity and mental health Does childhood obesity hinder human capital development?

Introduction

The association between obesity and depression is well established, with bi-directional associations widely reported in observational studies (Milaneschi et al., 2019). Recent Mendelian Randomization (MR) studies have confirmed a causal relationship between obesity and depression (Tyrrell 2019). Poor mental health has been proposed as one mechanism through which obesity during childhood may lead to poorer social and economic outcomes in later life (Segal et al., 2021). It was recently shown in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort that depressive symptoms mediated approximately 11% of the relationship between body mass index (BMI) and General Certificate of Secondary Education (GCSE) scores in girls, demonstrating the importance of mental health to human capital development (Bowman et al., 2022). Both psycho-social and biological mechanisms appear to be important in the causal chain from obesity to depression. The role of psycho-social mediators such as bullying and social stigma has been relatively well-described in population studies (Gini and Pozzoli, 2009; Moore et al., 2017). However, biological mechanisms may explain a significant proportion of the association between obesity and depression in children, which may have implications for policy interventions to improve mental health.

Proposed biological pathways in the causal pathways between obesity and mental health include alterations to the hypothalamic–pituitary–adrenal (HPA) axis, immuno-inflammatory activation, neuroendocrine regulators of energy metabolism, and the microbiome (Marazziti et al., 2014; Milaneschi et al., 2019). Biological mechanisms may be traced using biomarkers such as DNA methylation, an important regulator of gene expression, and metabolites, small molecules that reflect metabolic alterations. Obesity induces widespread changes in methylation levels across the genome (Wahl et al., 2017; Campanella et al., 2018) that may play a role in mood disorders. Differential methylation of a handful of the same genes involved in inflammatory pathways has been identified across separate studies of obesity and mood disorders (Gharipour et al., 2020). In addition, evidence shows BMI-associated DNA methylation predicts diseases, including T2D and cancers (Wahl et al., 2017). Similarly, as a metabolic disorder, obesity leads to widespread perturbation of the metabolome, which may influence mood. For instance, branched-chain amino acids (BCAAs) may influence brain function by modifying large, neutral amino acid transport at the blood–brain barrier, interfering with neurotransmitter synthesis (Fernstrom, 2005) (Gruenbaum et al., 2019). Recent reviews of the effects of obesity on the epigenome and metabolome in children identified consistent increases in both BCAAs and aromatic amino acids (AAAs) (Handakas et al., 2021) and methylation at multiple CpGs (sites of DNA methylation), albeit with less consistency between studies (Alfano et al., 2021).

In this study, we investigated the role of obesity-related metabolic and epigenetic signatures (measured through nuclear magnetic resonance (NMR) spectroscopy and DNA methylation array, respectively) in the onset of poor mental health in childhood in the ALSPAC cohort. We aimed to test the role of metabolites and differentially methylated CpGs as mediators of the relationship between childhood obesity and subsequent poor mental health or depression, assessed through the Short Mood and Feelings Questionnaire (SMFQ).