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Body weight regulation models in humans: insights for testing their validity

Nature Reviews Endocrinology volume 21, pages 703–717 (2025)Cite this article

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Abstract

Maintaining a ‘healthy’ body weight is crucial for survival and involves a partially understood regulatory system that adjusts energy intake and energy output (expenditure and losses) for that purpose. Several models of body weight regulation exist, but experiments testing their validity are lacking. This Review elaborates on how to test the validity of body weight regulation models in humans. We begin by highlighting the interaction between the obesogenic environment and the individual’s biological sensitivity to such environment, which triggers obesity in many, but not all, individuals. We discuss the identity of the regulated parameter(s), often considered to be body weight or body adiposity. We then focus on two models: set point and dual-intervention point. Under the set point model, obesity results from a malfunction of the system (leptin resistance) for preventing weight increases above the defended value. Under the dual-intervention point model, obesity occurs because the system tolerates a wide range of weights in some individuals. This key difference predicts different compensatory responses to energy balance perturbations in individuals according to their weight status, thus becoming instrumental in testing the validity of the models. Finally, we discuss the design of proof-of-concept experiments to advance the understanding of body weight regulation in humans.

Key points

  • The biological mechanisms that regulate body weight in humans are incompletely understood, yet their interaction with the environment determines body weight.

  • The nature of the regulated parameter, often considered to be body weight, is indeed unknown. Adiposity, lean mass and glycogen stores, among other parameters, are also potential candidates.

  • Different body weight regulation models have been proposed, which exert their regulation by triggering compensatory responses in energy intake and energy output (energy expenditure and energy losses).

  • The set point model proposes that body weight is defended at a fixed level, whereas the dual-intervention point model proposes that body weight is maintained between two boundaries, that is, the lower and upper intervention points.

  • We discuss key aspects for the design and interpretation of experiments aimed at testing the validity of body weight regulation models in humans, with a focus on comparing the set point and the dual-intervention point models.

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Fig. 1: BMI is a function of the obesogenic environment intensity and biological sensitivity to the obesogenic environment.
Fig. 2: Models of homeostatic regulation.
Fig. 3: Metabolic and compensatory responses to energy deficit.
Fig. 4: Predicted body weight according to the broadness of the zone of indifference in the dual-intervention point model and the intensity of the obesogenic environment.

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Acknowledgements

The authors thank V. Cortés for critical reading and recommendations to improve the manuscript. The authors are grateful to M. Heaner for her assistance with proofreading the manuscript. The authors acknowledge support from ANID/CONICYT FONDECYT Regular 1220551 (J.E.G.) and a NORC Center Grant #P30DK072476 titled ‘Nutrition and Metabolic Health Through the Lifespan’ sponsored by NIDDK.

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  1. Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA

    Rodrigo Fernández-Verdejo, Eric Ravussin & Jose E. Galgani

  2. Centro de Fisiología del Ejercicio y Metabolismo, Escuela de Kinesiología, Facultad de Medicina, Universidad Finis Terrae, Santiago, Chile

    Rodrigo Fernández-Verdejo

  3. Departamento de Nutrición y Dietética, Escuela de Ciencias de la Salud, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Jose E. Galgani

  4. Departamento de Nutrición, Diabetes y Metabolismo, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Jose E. Galgani

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Fernández-Verdejo, R., Ravussin, E. & Galgani, J.E. Body weight regulation models in humans: insights for testing their validity. Nat Rev Endocrinol 21, 703–717 (2025). https://doi.org/10.1038/s41574-025-01149-1

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