Evolution of energetics – in defense of fat

The human body is incredibly adept at maintaining a stable body weight over time. An average daily intake of 2,000 kcal equates to 730,000 kcal per year, and yet the “energetic error,” as indicated by an increase in body weight, is just over 1 pound per year [from observational data, NHANES (1)]. These observations led to the development of Set Point Theory (2), which posited that there is a signal from adipose to a receptor in the arcuate nucleus of the hypothalamus [the most probable candidate for this signal is leptin (3)], which leads to alterations in metabolism and physiology (a negative feedback loop) that support the maintenance of an individual’s body weight within a narrow, pre-determined range. This theory explains the strong genetic contribution to adiposity and the failure of dieting to promote long-term weight loss. However, it does not explain why individuals gain weight as they age, when they marry, and when they migrate to western countries, for example. Furthermore, fatally, Set Point Theory cannot explain the observed secular trends in obesity over the past four decades.

In order to address these limitations, the Settling Point Theory was developed (4). In addition to considering the homeostatic pressures introduced in Set Point Theory, this theory integrates two additional non-homeostatic pressures that influence body weight: environmental and behavioral pressures. The analogy used to demonstrate this theory is the level of water in a lake (5): the volume of water (adipose) is not actively regulated (nor does it have an active feedback signal), but as a result of rain (energy intake) and a dam (energy expenditure), the level of the lake naturally “settles” at some level as if it was regulated; that is, there is a dynamic equilibrium. If the amount of rain decreases, the level of the lake will decrease until it reaches the level of the dam, at which point the level of the lake will stop decreasing and remain at that new, stable level until another perturbation in rain.

One of the problems with Settling Point Theory is that it requires at least one parameter on the inflow or outflow to be regulated by the reservoir level and at least one parameter not to be regulated by the reservoir level (5). However, there is evidence to support that both food intake (6) and energy expenditure (7) are related to changes in adiposity. This is precisely why the 3,500 kcal per pound of fat rule fails: it assumes a linear relationship between net energy intake and body weight when the relationship is in fact asymptotic. Weight gain will not continue indefinitely if an individual permanently increases daily caloric intake by a small, fixed amount. This phenomenon stems from the fact that as his weight increases, the energy required to maintain that extra tissue also increases, thereby balancing the equation; and the converse occurs when weight decreases.

When an individual loses weight, his body responds by executing numerous metabolic and physiological adaptations to defend his body weight. These include decreasing leptin levels (decreasing nutrient signaling to the homeostatic regulator), enhancing insulin sensitivity (increasing lipid storage), favoring carbohydrate over fat metabolism (lipid-sparing metabolic state; higher caloric efficiency in weight relapse), and decreasing satiety signals from the hypothalamus (increasing drive to eat) (8). Two recent weight-loss studies (9, 10) have reported that there is long-term (1 year) persistence of hormonal and thermogenic adaptations to weight loss: higher ghrelin (stimulates hunger), and lower PYY and amylin levels (promote satiety) as well as lower thermogenesis and non-resting energy expenditure relative to baseline among those with sustained weight loss.

Energy requirements are proportional to body size. Therefore, in order to maintain weight loss one must continue to reduce caloric intake and in order to maintain settling weight (e.g. prevent weight gain after achieving weight loss) one must continue to consume a reduced calorie diet. The implication of this is that any one change in energy intake or expenditure will produce compensatory mechanisms that limit long-term effects of that change on body weight. This is precisely why reducing caloric intake by 100 kcal per day will not prevent weight gain with age. This is also why finding a pharmacological agent to treat obesity is an impossible challenge: targeting a single protein or metabolite will only address one part of a very complex system designed to maintain adiposity.

The most recent theory for understanding energy balance (11) combines Set Point Theory and Settling Point Theory in order to address the interaction between genetics and the environment in the determination of body weight (Figure).

A general model of body weight regulation. Compensated factors are those influenced by food intake and uncompensated factors are those not influenced by food intake. Genetics determine the level of impact that each of the factors has on body weight, thereby explaining individual differences in response to the same obesogenic environment.

Examples of compensated factors include blood glucose, free fatty acids, leptin, body fat mass, insulin, and body temperature; factors that have a particular, defended level. Compensatory responses tend to be relatively weak (particularly on a meal-to-meal and day-to-day basis) and transitory, explaining some of the mixed evidence relating to these factors. Furthermore, compensatory responses appear to be stronger with decreases in weight relative to increases in weight, explaining why gaining weight is typically easier than losing weight. Examples of uncompensated factors include social facilitation, taste, cost, availability, energy density, and portion size. Contrary to compensated factors, uncompensated factors can have a substantial impact on intake and body weight and should therefore be the targets for interventions.

Although this general model improves upon previous theories by recognizing gene-environment interactions, it continues to (inappropriately) use a reductionist, rather than holistic (systems), approach. Future research should focus on agent-based models (ABM) to explore the interactions of various individual and population risk factors over time in producing secular trends in obesity.


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