Obesity is a complex phenotype reflecting the interactions of numerous genes that have been “selected” for in service of reproductive integrity with modern environments. Attempts to lose weight and keep it off tend to “provoke” varying degrees of hypometabolism and hyperphagia which can be restrained, often only temporarily, by pharmacological and lifestyle interventions. In most lifestyle, pharmacological, and surgical interventions, weight loss occurs over an approximately 6-9 month period and is followed by a weight plateau period and then weight regain. Overall, only about one out of six of individuals are able to sustain a 10% or greater non-surgical weight loss. A key question is the degree to which the genotypes, phenotypes, and environmental correlates of success in weight loss and reduced weight maintenance are continuous or dichotomous. This is a comparison of the interactions of weight loss and reduced weight maintenance (success in avoid weight regain) with genetic, behavioral, physiological, and environmental homeostatic systems and a discussion of the implications of these findings for the treatment of obesity.

Correlations of genetic, phenotypic, and environmental factors with the likelihood of losing weight versus the likelihood of keeping it off suggest that there are differences in the “inner machinations” opposing weight loss and reduced weight maintenance. This is further support by studies examining the differences in short- and long-term responses to therapies designed to maintain negative energy balance (weight loss) versus prevention of weight regain (weight maintenance) following otherwise successful weight reduction. Overall, there is a continuum of responses between active weight loss and the plateau of reduced weight maintenance that are quantitatively different. The molecular physiological bases of weight regain, and their interactions with environment and lifestyle, include some of these same factors/mechanisms, but there are likely novel covariates as well.

The genotypic, phenotypic, and environmental predicates of the success at weight loss and sustaining it are highly heterogeneous. Overall, these data suggest that treatments to sustain weight loss are more likely to be successful if they are specifically directed at weight loss maintenance as distinct process with different physiological and behavioral context. This creates a clear opportunity for precision medicine approaches to both these processes with therapies that address the most salient risk factors in any given individual. Interventions to treat, or even prevent, obesity could be better leveraged to yield algorithmic approaches to current interventions and guide the development of new ones based on genotypic, phenotypic, and environmental factors to maximize effectiveness.

CME/CE Expiration Date: 10/28/26

*The expiration date listed above is the last day CME/CE credit can be claimed for this specific presentation.