Metabolic adaptation: is it really an illusion?

More than 70 y ago, Dr Albert Stunkard identified that weight loss treatments often fail due, in part, to the difficulty in maintaining weight loss. He famously stated, “Most people will not stay in treatment for obesity. Of those who stay in treatment, most will not lose weight and of those who do lose weight most will regain it” (1). Since then, weight loss strategies have improved, and many lifestyle interventions are now achieving levels of weight loss that are sufficient to confer significant improvements in cardiometabolic health (2). Nonetheless, after weight loss, most individuals return to their baseline weight within 5 y.

It is now well accepted that lower energy expenditure and higher physiological and psychological drivers of food intake undermine the ability to maintain weight loss. In a recent provocative study in 71 participants, Martins and colleagues (3) show that metabolic adaptation at the level of resting metabolic rate (RMR) is indeed present and quite variable (−92 ± 110 kcal/d) after 8 wk of energy restriction leading to significant weight loss (14 kg on average). After 4 wk of weight stabilization, this adaptation decreased to −38 ± 124 kcal/d on average. Furthermore, the authors report that the observed metabolic adaptation was not related to weight regain 1 y later. This prompted their conclusion that metabolic adaptation is a transient phenomenon—related to acute negative energy balance—which has nothing to do with weight regain. Despite this small study, there are ample data pointing to the impact of energy expenditure (including metabolic adaptation) on the regulation of body weight, even if energy intake seems to remain the major driver of weight loss relapse.

From early studies in the Pima Indians, a population prone to obesity, we identified that RMR was a familial trait likely genetically determined (4) and that a low metabolic rate for a given body weight and body composition was a risk factor for body weight gain (5). Our data suggested for the first time that the physiological variability in energy expenditure was an important biological factor underlying the propensity for weight gain and the resistance to weight loss in response to energy restriction. Importantly, we suggested that weight gain—and often obesity—was the price to pay to achieve a “normal” metabolic rate at a new higher energy flux (6).

As observed by Martins et al., RMR is often reduced by weight loss to a greater extent than would be expected by the loss of fat-free mass and fat mass. This physiological mechanism, called “metabolic adaptation,” represents one of the reasons why the body resists further weight loss and individuals regain weight so easily. In the classical Minnesota semistarvation studies, Keys et al. (7) reported first that RMR was drastically reduced in response to 24 wk of severe energy restriction, and well below the metabolic rate needed to support the reduced body mass. Years later, Leibel et al. (8) documented significant reductions in energy expenditure after weight loss in lean and obese adults beyond the predicted reductions due to the loss of fat-free mass and fat mass. Importantly, and unlike the data from Martins et al., this metabolic adaptation triggered by weight loss persisted years later (9). In another example, individuals participating in The Biggest Loser competition experienced an even larger metabolic adaptation (∼300 kcal/d) after a 40% body weight loss (10), which was sustained 6 y later despite an almost 70% regain of the initial weight loss (11). Interestingly, the magnitude of the observed metabolic adaptation was strongly related to the degree of negative energy balance during weight loss and the reduction in plasma leptin concentration (12).

In an impressive series of prospective studies in which metabolic adaptation was measured in response to acute episodes of overfeeding or fasting, Piaggi (13) identified “thrifty” and “spendthrift” phenotypes associated with resistance or ease of losing weight during caloric restriction. These prospective observations once again emphasize the role of energy expenditure in the control of body weight and in the maintenance of weight loss. As such, we are somewhat surprised that Martins et al. dismiss the role of RMR and metabolic adaptation in body weight regulation. We agree that the impact of metabolic adaptation on energy balance can be rather small (∼6% of 24-h energy expenditure); however, the variance among individuals is considerably larger—for example, ±110 kcal/d after weight loss in the Martins study. However, as we initially proposed, because an impaired energy expenditure can explain only a small fraction of the weight gain, a low RMR can also be a marker for either enhanced hunger or impaired satiation and therefore hyperphagia (14). Confirming such a hypothesis in 50 study participants, energy restriction was shown to impact circulating mediators of appetite immediately after weight loss, with an elevation of orexigenic signals and a reduction of anorexic signals, even 1 y after the initial weight loss (15).

In contrast to Martin and colleagues’ observations and claims, the literature indeed suggests that persistence of metabolic adaptation is likely to play a role in the lack of success in maintaining the weight loss. However, there remains a critical need to identify and understand the mechanisms that drive weight regain as well as those that promote long-term weight loss maintenance. To date, very few trials have studied the effect of changes in potential mediators of energy expenditure and energy intake on weight loss and subsequent weight regain and none in a single study. For these reasons, a workshop was organized last year by the National Institutes of Health which resulted in a Request For Applications to create a research consortium to tackle these questions using state-of-the-art energy balance methods and improve our understanding of the mechanisms of weight loss maintenance (https://grants.nih.gov/grants/guide/rfa-files/rfa-dk-19-017.html). Until the results of these experiments are known, a more balanced view of the literature surrounding metabolic adaptation and body weight regulation is required. Casting a dismissive view of metabolic adaptation “as an illusion” with this 1 study—after so many others have shown its importance—is problematic to say the least.

Notes

The authors report no conflicts of interest.