Models of body-weight regulation: set-point, settling-point, and the thrifty and drifty gene hypotheses

Cite as: Leatham E. Models of body-weight regulation: set-point, settling-point, and the thrifty and drifty gene hypotheses. VAT-Trap / SCVC Cardiometabolic Series. Surrey Cardiovascular Clinic; 2026. doi:10.5281/zenodo.21096688

This white paper reviews the principal scientific models proposed to explain long-term regulation of human body weight. It compares the classical set-point model, the settling-point (dynamic equilibrium) model, several hybrid and control-theory models, and the dual-intervention-point (DIP) model. The paper then examines two competing evolutionary explanations for individual susceptibility to obesity: the thrifty-gene hypothesis and the drifty-gene hypothesis. Evidence from leptin biology, metabolic adaptation, evolutionary theory, and weight regain following discontinuation of GLP-1 receptor agonists is critically appraised. Rather than advocating a single theory, the review concludes that current evidence supports a continuum of regulatory mechanisms and that no existing model fully explains observed human physiology. The paper is intended as an educational resource for clinicians, researchers, and patients interested in obesity, body-weight regulation, and the biological mechanisms underlying visceral adiposity and long-term weight management.

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