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Review
. 2011 Nov;4(6):733-45.
doi: 10.1242/dmm.008698.

Set Points, Settling Points and Some Alternative Models: Theoretical Options to Understand How Genes and Environments Combine to Regulate Body Adiposity

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Review

Set Points, Settling Points and Some Alternative Models: Theoretical Options to Understand How Genes and Environments Combine to Regulate Body Adiposity

John R Speakman et al. Dis Model Mech. .
Free PMC article

Abstract

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.

Figures

Fig. 1.
Fig. 1.
The lipostatic model of body fat regulation. This model was first suggested by Kennedy (Kennedy, 1953) and widely adopted in the 1990s following the discovery of leptin. In this model, fat tissue produces a signal (generally presumed to include leptin) that is passed to the brain, where it is compared with a target (the set point of the system) (A). Discrepancies between the level of the signal and the target are translated into effects on energy expenditure and energy intake to equalise the discrepancy and maintain homeostasis. That is, if the signal is too high (as in B, where body fatness is above the target level), expenditure is increased and intake decreased until fatness falls and the signal and target are brought back in line. Conversely, if the signal is low relative to the target (as in C, where the individual is too thin as determined by the set point), intake is increased and expenditure is reduced to drive the subject into a positive energy balance, resulting in an increase in fatness and bringing the target and signal back in line.
Fig. 2.
Fig. 2.
An example of a settling point system: levels of water in a lake. (A) In this schematic, the input to the lake is rain falling in the hills. The output of water from the lake is directly related to the depth of water at the outflow. The depth of the water in the lake reaches a settling point at which the outflow is equal to the inflow (indicated by the sizes of the arrows). (B) If the amount of rainfall increases (denoted by the larger arrow), the level of water in the lake increases until a new settling point is reached, at which the outflow is equal to the inflow. (C) Conversely, if the amount of rainfall decreases, the water level in the lake falls until a new settling point is reached, again where the outflow matches inflow. (D) The key characteristics of the settling point system are that a parameter of interest (e.g. body energy stores) has both inputs (energy intake) and outputs (energy expenditure). Importantly, for a settling point system to operate, one of these parameters must be independent of the size of the parameter of interest, and the other must vary in direct relation to the size of the given parameter (in this case the expenditure). The resulting settling point of the system varies in direct proportion to the unregulated flow.
Fig. 3.
Fig. 3.
The general model of intake regulation. This model is from de Castro and Plunkett (de Castro and Plunkett, 2002). In the model, intake (I) is controlled by two sets of factors, labelled as uncompensated (Ui; primarily environmental) and compensated (Ci; primarily physiological) factors. A key difference between these types of factors is that compensated factors have negative feedback loops with intake, simultaneously affecting and being affected by intake, whereas uncompensated factors affect intake, but are not affected by intake. Inheritance affects the system by determining: the preferred level for intake and compensated and uncompensated factors; the level of impact of the compensated (WCi) and uncompensated (WUi) factors on intake; and also the level of impact of intake minus expenditure (I–E) on compensated factors (i.e. WFi; the weighting factor). The model combines the concepts of negative feedback inherent in the set point model and uncompensated factors inherent in the settling point model.
Fig. 4.
Fig. 4.
Simulated responses of the general intake model. This figure was reproduced, with permission, from de Castro and Plunkett (de Castro and Plunkett, 2002); see also Fig. 3 and main text. The model’s response to a simulated change in the environment was investigated by doubling the level of one uncompensated factor. In response to the change, the body weight became unstable and oscillated before stabilising at a higher body weight. When the weighting factor was low, the doubling of the uncompensated factor produced only a small increase in body weight. But when the weighting factor was large, the model’s output reflected a large increase in body weight.
Fig. 5.
Fig. 5.
The dual intervention point model. This model is illustrated here by changes in body weight over time. The body weight varies depending on the prevailing direction of the environmental pressures. In period A, these pressures largely favour weight loss, and the body weight or adiposity declines. In period B, these factors largely favour weight gain and body mass increases. At these times weight is largely dictated by environmental factors. However, at C, the pressure to gain weight has resulted in weight increasing to the upper intervention point. Further weight gain is resisted by physiological (genetic) factors (depicted by black arrow). The weight therefore remains in balance: declines are prevented by the upward environmental pressures, and increases are prevented by physiological factors. Weight will only start to decline again (D) when the environmental pressure to increase weight is reversed (or an intervention is started). In any situation in which there is a constant environmental pressure favouring weight gain, individuals will increase to their upper intervention points, which vary among individuals and are hypothesised to be genetically determined. (Similarly, weight loss becomes resisted at the lower intervention point by other physiological mechanisms: not illustrated here.) This model also combines the ideas of settling points and uncompensated factors, which dominate between the intervention points, and physiological feedback controls that operate when the intervention points are reached.

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