Abstract / Summary
The global obesity epidemic continues despite intensive research, in part because the dominant conceptual framework remains the energy balance model. This paradigm has struggled to reconcile the high heritability of body mass index (40–70 %) [1] with the small effect sizes of common variants identified by genome-wide association studies (GWAS), which collectively explain only a few percent of BMI variance [2–4]. Here I argue that the missing heritability of obesity is, to a substantial degree, an artifact of phenotype resolution. GWAS has asked which genes regulate energy balance; the genes regulate mass balance. The body possesses no receptors for calories or joules. It senses the mass and molecular identity of specific nutrients. Reframing the three canonical obesity genes through the mass balance model (MBM) yields a complete account of macronutrient partitioning: FTO regulates nitrogen mass balance, MC4R regulates carbon mass partitioning, and leptin regulates lipid mass clearance. These three genes describe the three mass fluxes that constitute body-weight regulation. The framework generates precise, falsifiable predictions and identifies new GWAS endpoints – most importantly the mass-clearance parameter k – that lie closer to the immediate targets of gene action than BMI. Measuring k, rather than a coarse anthropometric surrogate, offers the most direct route to recovering the missing heritability.