Molecular Mechanisms of Metabolic Adaptation to Weight Change

May 2019 Council

Lead Division/Office

ONR / DDN / DEM

Point(s) of Contact

Maren Laughlin, Ph.D.

Executive Summary

Obesity rates continue to rise in the U.S. While significant weight loss can be achieved by a combination of dietary restriction and increased physical activity, only ~15% of individuals with obesity succeed in maintaining weight loss in the long-term. Among other factors underlying this problem of weight relapse is weight change-related activation of compensatory appetitive and metabolic responses. This concept proposes to focus on compensatory metabolic adaptation. Evidence in humans began to emerge in the 1980s, inferring that physiological mechanisms exist that allow for homeostatic adjustments to our metabolic efficiency in response to changes in body weight. Not to be confused with metabolic flexibility, the metabolic adaption refers to changes in efficiency with which the body converts calories to chemical or physical work (estimated to be ~25-40% efficient, i.e. most calories are wasted as heat or otherwise lost). Classic studies at the Rockefeller University found that decreased efficiency following 10% weight gain led to 450-500 calories more of total daily energy expenditure, while increased efficiency after 10% weight loss resulted in 300 fewer calories needed to support the new weight, considerably less than that anticipated based on body mass. These findings have been repeated many times including at intramural NIH. What this means is that as we try to maintain lost weight our body fights this perturbation by becoming more efficient. While adipose tissue is an obvious target for this adaptation, the changes in energy efficiency are most convincingly demonstrated using a low intensity exercise on an ergometer that can measure energy output before and after weight change, and may therefore manifest in skeletal muscle. Understanding the mechanisms of this ability to become more (weight loss) or less (weight gain) efficient in the use of energy, and the duration of this phenomenon, could reveal new therapeutic targets for obesity intervention, aimed at maintaining weight loss.

Molecular factors in obesity have been identified, but we do not know the pathways responsible for altered energy efficiency with changes in weight. The many discovery tools that are available today combined with pathway analyses and bioinformatic tools offer opportunities to identify them in human populations. Applying these technologies now to metabolic adaptation might reveal potential mechanisms and opportunities for therapeutic lifestyle and drug interventions that would allow people to be more successful in their weight loss and maintenance.