Set points, settling points and some alternative models: Theoretical options to understand how genes and environments combine to regulate body adiposity

John R. Speakman*, David A. Levitsky, David B. Allison, Molly S. Bray, John M. De Castro, Deborah J. Clegg, John C. Clapham, Abdul G. Dulloo, Laurence Gruer, Sally Haw, Johannes Hebebrand, Marion M. Hetherington, Susanne Higgs, Susan A. Jebb, Ruth J.F. Loos, Simon Luckman, Amy Luke, Vidya Mohammed-Ali, Stephen O'Rahilly, Mark PereiraLouis Perusse, Tom N. Robinson, Barbara Rolls, Michael E. Symonds, Margriet S. Westerterp-Plantenga

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

223 Citations (Scopus)
10 Downloads (Pure)


The close correspondence between energy intake and expenditure over prolonged time periods, coupled with an apparent protection of the level of body adiposity in the face of perturbations of energy balance, has led to the idea that body fatness is regulated via mechanisms that control intake and energy expenditure. Two models have dominated the discussion of how this regulation might take place. The set point model is rooted in physiology, genetics and molecular biology, and suggests that there is an active feedback mechanism linking adipose tissue (stored energy) to intake and expenditure via a set point, presumably encoded in the brain. This model is consistent with many of the biological aspects of energy balance, but struggles to explain the many significant environmental and social influences on obesity, food intake and physical activity. More importantly, the set point model does not effectively explain the 'obesity epidemic' - the large increase in body weight and adiposity of a large proportion of individuals in many countries since the 1980s. An alternative model, called the settling point model, is based on the idea that there is passive feedback between the size of the body stores and aspects of expenditure. This model accommodates many of the social and environmental characteristics of energy balance, but struggles to explain some of the biological and genetic aspects. The shortcomings of these two models reflect their failure to address the gene-by-environment interactions that dominate the regulation of body weight. We discuss two additional models - the general intake model and the dual intervention point model - that address this issue and might offer better ways to understand how body fatness is controlled.

Original languageEnglish
Pages (from-to)733-745
Number of pages13
JournalDMM Disease Models and Mechanisms
Issue number6
Publication statusPublished - 7 Nov 2011

Bibliographical note

We are grateful to The Company of Biologists for funding the workshop that led to this paper. We also thank Nicky Le Blond for her exceptional organisational skills displayed before, during and after the meeting, and ‘Bo’ Bogardus and Emily Dhurandhar for their perceptive comments on the manuscript.


Dive into the research topics of 'Set points, settling points and some alternative models: Theoretical options to understand how genes and environments combine to regulate body adiposity'. Together they form a unique fingerprint.

Cite this