Mass Balance over Energy Balance: Why Direct Mass Accounting Offers a More Precise and Mechanistically Faithful Framework for Human Body Weight Regulation

The energy balance model (EBM) and its operational form, calories-in-calories-out (CICO), have dominated obesity research and clinical practice for decades. While these frameworks have yielded valuable public health insights, they rely on indirect conversions between mass and energy and rest on misconceptions about thermodynamic principles. This Perspective argues that a mass balance model (MBM) provides a conceptually simpler, mathematically consistent, and biologically more faithful paradigm. By tracking macronutrient mass directly – without intermediate energy-unit conversions or misapplications of thermodynamic laws – the MBM aligns analysis with physiological reality and better predicts body composition dynamics. Clarifying that the first law of thermodynamics concerns only energy (not mass), that calories cannot be eaten or oxidized, and that E=mc² has no relevance to human metabolism paves the way for more precise translational interventions in metabolic medicine.