Changes in Body Composition including Muscle with Anti-Obesity Medications, both with and without Exercise - Contemporary pharmacotherapies for obesity treatment are considered nutrient stimulated hormone receptor agonists (NuSH-RA) therapies because they target the receptor and attempt to mimic naturally occurring NuSHs in the body that contribute to the regulation of energy intake and eating behavior (e.g., GIP and/or GLP-1). These current NuSH-RA therapies are highly efficacious for weight loss and related comorbidities in adults with obesity. Weight loss with NuSH-RA therapies has been primarily attributed to the loss of adipose tissue; however, this may also be accompanied by a significant loss of lean mass, which has been estimated to range from 25-40% based on available data. Of importance, we posit that lean mass is not a surrogate for muscle mass, and studies of NuSH-RA therapies have not measured muscle mass. Therefore, it is unclear if the change in lean mass reflects changes occurring with muscle mass. To address this important clinical research question, in addition to measuring lean body mass, we will also use the validated deuterated creatine (D3Cr) dilution method for a direct and accurate assessment of muscle mass, and we include the co-inventor of this novel methodology as a co- investigator on this project. The addition of exercise to NuSH-RA therapies for obesity may assist in the preservation of lean mass, and specifically muscle mass. However, there are currently no published randomized clinical trials that evaluated the addition of either cardiovascular or resistance exercise training at the outset of NuSH-RA therapy for the treatment of obesity, and there is a lack of published studies that examined the effect of either mode of exercise on lean body mass or muscle mass when combined with a NuSH-RA therapy. Thus, examining these factors within the context of NuSH therapies, both with and without exercise, is of clinical importance and warrants examination. This proposed study includes both a cardiovascular exercise training (NuSH+CE) and resistance exercise training (NuSH+RE) to examine either mode of exercise is beneficial compared to NuSH alone. We hypothesize that an appropriate mode of exercise, when added to NuSH-RA therapy for obesity, can benefit retention of lean mass, muscle mass, and muscle quality. We propose a 6-month intervention in 198 patients prescribed NuSH therapy with randomization to: 1) standard care with NuSH therapy [NuSH], 2) NuSH+cardiovascular exercise [NuSH+CE], 3) NuSH+resistance exercise [NuSH+RE]. Our primary analyses will examine whether either of the exercise conditions (NuSH+CE, NuSH+RE) is superior to NuSH. Our primary and secondary outcomes include measures of body composition, muscle mass, muscle quality. We also include measures of cardiorespiratory fitness, muscle strength, physical function, bone mineral density and bone biomarkers. Measures of energy intake, physical activity, hunger, satiety, fullness, and food consumption are included. Additional moderator analysis to examine the effects of sex, race/ethnicity, and age are proposed. We will also conduct exploratory analyses to compare NuSH+CE vs. NuSH-RE on the study outcomes.
