Phenotype-Tailored Lifestyle intervention for Obesity: A Randomized Trial

PROJECT SUMMARY Obesity is a chronic, relapsing, and multifactorial disease, with a prevalence of 42%. Obesity treatment is challenging in clinical practice because of the physiologic and behavioral adaptations that occur during the weight-reduced state to preserve energy. Our overall goal is to develop an evidence-based, phenotype-guided

approach for obesity treatment that enhances weight loss and induces weight loss maintenance despite weight- reduced state adaptations. Our research has identified obesity phenotypes based on energy homeostasis and behavioral traits. Obesity phenotypes include abnormal satiation (i.e., requiring more calories at each meal to

achieve fullness), abnormal postprandial satiety (i.e., accelerated gastric emptying and increased postprandial hunger), emotional eating (i.e., eating in response to positive or negative emotions), and abnormal resting energy expenditure (i.e., low resting energy expenditure). In pilot clinical studies, these obesity phenotypes have

predicted weight loss response to anti-obesity medications and bariatric endoscopic devices. We recently published data from a 12-week proof-of-concept, non-randomized clinical trial of 165 patients in which 84 participants received lifestyle interventions designed for each phenotypic trait they had and 81 received standard

lifestyle recommendations. The phenotype-tailored lifestyle intervention (PLI) resulted in greater weight loss compared to the standard lifestyle intervention (SLI) approach for obesity. Patients in the PLI showed improvement of their phenotype-defining trait(s). Improvement in these traits may explain the greater weight loss

as they potentially counteract physiologic and behavioral adaptations of the weight-reduced state. To validate these data, we must study PLI in a longer-term and randomized clinical trial. Furthermore, the current methods used to identify phenotypes in our preliminary studies are time-consuming, invasive, expensive, limited to a few

academic centers, and not accessible for most patients. In an academic-industry partnership, we have developed a novel biomarker test that predicts obesity phenotypes but that needs to be validated in a large prospective cohort. As such, we have formulated the following central hypothesis: “tailoring lifestyle recommendations to

obesity phenotypes will enhance long-term weight loss outcomes in adult patients with obesity”. To test our central hypothesis, we propose a 12-month randomized, blinded, parallel clinical trial in adults with obesity to test three aims: 1) To compare the outcomes of PLI vs. SLI program; 2) After a 12-month weight loss

program, to compare the long-term effect of PLI compared to SLI on physiological (i.e., satiation, postprandial satiety, energy expenditure) and behavioral (i.e., emotional eating) adaptations; and 3) To explore whether a phenotype biomarker predicts weight loss in response to PLI compared to SLI. Significance: Our study has the

potential to introduce an individualized treatment that targets pathophysiological and behavioral phenotypes of energy balance to enhance and maintain weight loss outcomes.