Adaptive Mechanisms Responsible for Weight Regain in Youth with Obesity and the Influence of Sex

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Project Summary / Abstract Pediatric obesity is a pervasive problem in the United States. While short-term weight loss can be achieved in a high proportion of adolescents with obesity the ability to prevent subsequent weight and fat mass regain long-term is extremely challenging. The mechanisms underlying weight and fat mass regain in adolescents with obesity are poorly defined and will be determined by this study. Neuroendocrine changes in the gut-brain axis (influencing appetite and satiety) and metabolic adaptation (changes in energy expenditure and regulation) have been identified as key mechanisms contributing to weight and fat mass regain after weight loss in adults. Whether these adaptive responses are applicable to pubertal adolescents remains unknown. Presuming that adult mechanisms are applicable to pediatrics is premature, adolescents undergo unique and dynamic changes, such as sex-specific developmental growth and puberty-driven hormonal alterations, which could influence the biology regulating energy balance in a fundamental way contributing to fat mass accumulation. Gaining a better understanding of the underlying mechanisms driving fat mass regain following weight loss during adolescence will advance the current paradigm for treating pediatric obesity towards, 1) optimizing the timing and intensity of treatment, 2) tailoring therapies based on sex-specific developmental characteristics, and 3) lead to new intervention strategies. We propose a study to identify the biological mechanisms and health behaviors driving weight and fat mass regain among adolescents (11 to 15 years old) with obesity by carefully considering the impact of sex-differences. We will use an established approach of short-term (8 weeks) meal replacement therapy to elicit weight loss (≥5% BMI reduction). Following successful weight loss, we will follow individuals (n=100) on lifestyle modification therapy for 26 weeks where we expect a wide-range of responses ranging from continued weight and fat mass loss, maintenance of weight and fat loss, and weight and fat mass regain. To examine the impact of sex, we will have an even distribution of males and females at baseline, and we will carefully examine the biological influence of sex-specific differences. Our primary outcome will be change in total fat mass (kg) measured by dual energy x-ray absorptiometry. Our overall hypothesis is that changes in energy expenditure and appetite and satiety regulating hormones will independently explain the variability in fat mass trajectories, with sex-specific differences playing an important role in mediating these relationships. This study will identify new treatment targets to enhance weight loss maintenance in adolescents with obesity by: 1) uncovering the key aspects of energy regulation and appetite/satiety hormones promoting fat mass regain and; 2) determining sex-specific factors to inform tailored therapies to prevent fat mass regain.