Dieting is the most common approach to losing weight for the majority of obese and overweight individuals. Restricting intake leads to weight loss in the short term, but, by itself, dieting has a relatively poor success rate for long-term weight reduction. Most obese people eventually regain the weight they have worked so hard to lose. Weight regain has emerged as one of the most significant obstacles for obesity therapeutics, undoubtedly perpetuating the epidemic of excess weight that now affects more than 60% of U.S. adults.
In this review, we summarize the evidence of biology’s role in the problem of weight regain. Biology’s impact is first placed in context with other pressures known to affect body weight. Then, the biological adaptations to an energy-restricted, low-fat diet that are known to occur in the overweight and obese are reviewed, and an integrative picture of energy homeostasis after long-term weight reduction and during weight regain is presented.
Finally, a novel model is proposed to explain the persistence of the “energy depletion” signal during the dynamic metabolic state of weight regain, when traditional adiposity signals no longer reflect stored energy in the periphery. The preponderance of evidence would suggest that the biological response to weight loss involves comprehensive, persistent, and redundant adaptations in energy homeostasis and that these adaptations underlie the high recidivism rate in obesity therapeutics. To be successful in the long term, our strategies for preventing weight regain may need to be just as comprehensive, persistent, and redundant, as the biological adaptations they are attempting to counter.
In the united states, over 60% of adults and close to 20% of children are overweight or obese (35, 174). A number of effective weight loss strategies are available, but most are only transiently effective over a period of 3 to 6 mo. Less than 20% of individuals that have attempted to lose weight are able to achieve and maintain a 10% reduction over a year (128). Over one-third of lost weight tends to return within the first year, and the majority is gained back within 3 to 5 years (3, 246). A number of reasons have been proposed for the high incidence of weight regain (69, 246), and several point to the biological response to weight loss.
The objective of this review is to examine the role of this biological response in the process of weight regain. Biological regulation is first discussed in relation to other nonbiological pressures that affect body weight as weight is gained, lost, and regained. The specific biological adaptations to the most common form of dieting, an energy-restricted low-fat diet, are then discussed in more detail. Previous reviews provide extensive descriptions of the normal adaptive response to energy restriction. We do not attempt to recapitulate those efforts here. Rather, the unique perspective of this review summarizes those adaptations that have been confirmed or specifically observed in the overweight or obese. Because there are unique features of the adaptive response with obesity (138, 251, 252), understanding the integrative nature of the response in the obese is pertinent to therapeutic development.
Although homeostatic systems are clearly operational in both lean and obese individuals and, in both, underlie the tendency for lost weight to be regained, the central and peripheral adaptations involved in weight recovery can differ with one’s starting weight. These differences may provide insight as to what components of the homeostatic system would be most effectively targeted in those who have the most difficulty controlling their weight.
To this end, we examined weight loss studies in clinically overweight and obese adults, in diet-induced, polygenic animal models of obesity, and with dietary (nonsurgical) interventions involving an energy-restricted, low-fat diet. We would assert that, in contrast to its subtle, permissive role in the development of obesity, biology has a more prominent, causal role in weight regain after energy-restricted weight loss. Countering this metabolic drive to regain lost weight may be the most significant challenge for obesity therapeutics in the coming decades.
Our Biology in the Context of Other Pressures Affecting Body Weight
Body weight is affected by biological, environmental, and behavioral pressures, all of which are inherently influenced by genetics (Fig. 1). These pressures interact with one another, and their integrated effect establishes a “steady state” weight in adults. Humans exhibit a broad weight range, because of the variability in each of these pressures and the genetic diversity that underlies them. Changing any one of these pressures can alter the steady-state weight.
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