Causal Effects of Childhood BMI on Regional Fat Distribution in Adults: A Mendelian Randomisation and Proteomic Mediation Analysis

Childhood obesity is a major global health concern, yet the long-term effects of early-life adiposity on adult fat distribution and underlying biological pathways remain poorly understood. In particular, it is unclear whether childhood BMI differentially influences specific adipose tissue depots and whether circulating proteins mediate these relationships.

We conducted a Mendelian randomisation study using genetic instruments for childhood BMI across 12 timepoints from ages 3 to 18 years. Two-sample MR was applied to five MRI-derived adult fat depots (abdominal subcutaneous (ASAT), gluteofemoral (GFAT), visceral (VAT), liver, and pancreatic fat) in UK Biobank. We further implemented a two-step MR framework to assess whether 2,940 circulating plasma proteins (Olink) mediate observed associations, integrating temporal, statistical, and directional evidence across childhood.

Genetically predicted higher childhood BMI from approximately age 7 years onwards was associated with increased ASAT and GFAT in adulthood, but showed little evidence of association with visceral, liver, or pancreatic fat, with effects persisting into adolescence. Two-step MR identified 140 proteins influenced by childhood BMI during a developmentally sensitive window, of which seven showed directionally consistent evidence of mediation. These proteins included ACAN, CCL7, and CLIC5 for abdominal subcutaneous fat, and CLIC5, BMP10, CLEC10A, KIT, and IGSF3 for gluteofemoral fat, highlighting partially distinct biological pathways across depots.

Childhood BMI exerts depot-specific effects on adult fat distribution, particularly influencing subcutaneous adipose tissue. Circulating proteins provide evidence of potential mediating pathways, supporting the existence of developmentally sensitive biological mechanisms linking early-life adiposity to adult body composition. These findings underscore childhood as a critical period for shaping long-term adipose tissue distribution and highlight potential molecular targets for future intervention strategies.

Author Summary

How much fat someone carries as a child can shape their health for decades, but where that fat ends up in the body as an adult may matter just as much as how much there is. Fat stored under the skin behaves very differently, biologically, from fat stored around internal organs or within the liver — and these different patterns are linked to different health risks later in life. In this study, we used genetic data to test whether having a higher body weight in childhood causally influences how fat is distributed across the body in adulthood, rather than simply relying on correlations that could be explained by other factors. We also looked at levels of specific proteins in the blood to see whether they might help explain this link — acting as a biological bridge between childhood body weight and where fat settles later in life. By pinpointing proteins that may carry this influence forward, we hope to shed light on the biological pathways connecting early-life body weight to long-term patterns of fat distribution, which could inform future research into prevention or intervention strategies. This work is part of a broader research programme investigating how body fat distribution relates to health outcomes across the life course.