Predictors of Recidivism to Obesity in Weight-Reduced Individuals

Obesity is a major contributor to human illness and health care costs by virtue of its functional associations with type 2 diabetes, hypertension, fatty liver, dyslipidemias, various cancers, degenerative brain disease and, very recently, contribution to morbidity and mortality associated with SARS-CoV-2 infection. Modest weight loss can mitigate the severity – or entirely reverse - many of these phenotypes. Maintenance of a 10% reduced body in obese or lean individuals invokes homeostatic changes in energy expenditure (decreased) and hunger (increased) that tend to restore body weight. These changes are conveyed by persistent complex molecular- physiological processes in the brain and autonomic nervous systems, thyroid and leptin axes, skeletal muscle, and adipose tissue. Individuals differ in the intensity of these responses, perhaps accounting for differences in long-term success for weight loss maintenance. This study prospectively examines the behavioral and molecular physiology of these systems following a lifestyle-mediated 10% weight reduction in individuals with overweight or obesity, and examines the contributions of these factors to amount of weight regain in the one year period following achievement of the weight reduction during a period of minimum clinical intervention. Our Specific Experimental Aims are to: 1. Examine the behavioral, metabolic, and environmental impacts on success in sustaining 10% weight loss by measuring the association of (a) ad lib energy intake (EI), (b) 24h energy expenditure (EE); and (c) the individual’s food environment at reduced body weight on changes in body weight and fat mass one year following achievement of 10% weight reduction. 2. Assess the physiology of the weight-reduced state in dynamic circumstances in order to provide predictors of weight outcome at 12 months after 10% weight loss. EI and EE will be measured: (a) in response to a single dose of leptin administered after achievement of reduced body weight; (b) 6 months following weight loss. 3. Generate mechanistically-informed regression equations predicting change in body weight in the 12 months following 10% weight loss. “Endophenotypes” related to EI and EE will be measured in the weight- reduced state: food-choice task performance associated with food intake and fMRI activity in the dorsal striatum; sleep/circadian rhythms; skeletal muscle contractile efficiency (in vivo and ex vivo), plasma metabolomics /exposomics and endocrines, urinary catecholamines, gene expression and epigenetics of adipose tissue and muscle, and peripheral blood mononuclear cells. These endophenotypes, EI and EE, will be used to generate predictive equations that will quantify the relative contributions of these factors and suggest possible interventions to assist in long-term maintenance of reduced body weight.