Background

Childhood obesity has increased worldwide and is associated with elevated risk of cancer in later life. While childhood body mass index (cBMI) influences adult health, its long-term effects on regional adipose tissue distribution remain poorly characterised. Emerging evidence demonstrates distinct causal roles of regional adiposity in obesity-related cancer development. However, early-life determinants of regional depots, and biological mechanisms linking childhood adiposity to adult fat distribution and cancer risk remain unclear. Circulating proteins represent plausible mediators of these relationships, yet have not been evaluated systematically. Conventional observational studies are limited by confounding and reverse causation. Mendelian randomisation (MR), which leverages genetic proxies for traits of interest, provides a robust framework for causal inference.

Objectives

(i) Determine the relationship between cBMI and regional adult adiposity, across the lifecourse; and 
(ii) Identify underlying molecular mechanisms; and
(iii) Assess whether proteins influenced by early-life adiposity are causally linked to adult fat depots and obesity-related cancer outcomes.

Methods

We conducted a time-stratified MR study to investigate the causal effects of cBMI on adult fat distribution and to identify molecular mediators. Genetic instruments for cBMI were derived from the Norwegian Mother, Father and Child Cohort Study (MoBa) and replicated in the Avon Longitudinal Study of Parents and Children (ALSPAC), resulting in 12 timepoints between 3-18 years of age. Two-sample MR was used to estimate the effects of cBMI at each timepoint on five imaging-derived adult fat depots—ASAT, GFAT, VAT, liver fat, and pancreatic fat—using UK Biobank genetic summary statistics.
Timepoints demonstrating effects on adult fat distribution defined a critical window for mediation analyses. We then evaluated 2,940 circulating proteins using UK Biobank Olink protein data, selecting candidates based on association with cBMI within the identified window and depot-specific effects.
Finally, MR was used to assess the indirect effects of candidate proteins on ASAT- and GFAT-linked cancer outcomes identified.

Results

We observed little evidence of an effect of cBMI on adult fat depots between ages 3–6 years. From ~age 7 onwards, cBMI was positively associated with ASAT and GFAT. Instrument strength was modest (F-statistics mostly <10), indicating potential weak-instrument bias. However, consistency across sensitivity analyses (MR-LASSO, MR-PRESSO, Radial MR) increased robustness of these findings.
Of the 2,940 proteins assessed, sequential filtering identified three candidate mediators between cBMI and ASAT (ACAN, CLIC5, CCL7), and five for GFAT (CLIC5, BMP10, CLEC10A, KIT, IGSF3). We observed evidence of decreased overall breast cancer risk per SD increase in CCL7 (OR=0.95, 95% CI=0.89-1.00), independent of the cancer-associated fat depots. Meningioma, ovarian carcinoma, endometrial and hepatic cancers were also analysed, with no effects found.

Conclusions & Implications

Childhood BMI influences adult fat distribution in a time-dependent manner, with effects emerging in mid-childhood and preferentially promoting ASAT and GFAT deposition. Identification of candidate protein mediators implicates immune and cellular stress pathways in biological embedding of early-life adiposity. Mid-childhood may represent a critical window for intervention, and identified proteins may serve as targets for modifying long-term metabolic and cancer risk.