PROJECT SUMMARY/ABSTRACT Obesity is a growing epidemic, with more than two-thirds of adults in the United States overweight or obese. Although diet-induced weight loss reduces obesity-related complications, it is increasingly recognized that serious complications of weight loss occur, including fractures and sarcopenia. This is an important public health issue given the large number of adults seeking weight loss, and the increasing prevalence rates of osteoporosis and sarcopenia. However, little is known about the effects of different pharmacologic therapies for weight loss on bone and muscle. The proposed research will investigate whether the glucagon-like peptide 1 receptor agonist (GLP-1 RA), liraglutide, which is FDA-approved for the treatment of obesity, mitigates bone resorption and muscle mass loss associated with weight loss. If this is true, then liraglutide may be a preferred pharmacologic therapy for weight loss, especially in adults with obesity and osteoporosis or sarcopenia. Preclinical data suggest that GLP-1 RAs may be anabolic to bone and muscle. GLP-1 promotes bone formation while suppressing bone resorption in vitro. In rodent models, GLP-1 RAs increase bone density and strength and increase muscle mass. However, clinical data regarding the effects of GLP-1 RAs, as prescribed for weight loss, on bone metabolism markers, as well as muscle mass and strength, are lacking. Osteoblasts and adipocytes are differentiated from common mesenchymal bone marrow stem cells. Weight loss increases marrow adipose tissue (MAT), which can be measured by MR spectroscopy in humans, and is associated with decreased bone mineral density. In vitro data suggest that GLP-1 RAs inhibit marrow adipogenesis while promoting osteoblast differentiation, but whether decreasing MAT is a mechanism by which GLP-1 RAs affect bone mass in humans is not known. Our hypothesis is that 3 months of daily subcutaneous liraglutide will result in lower bone resorption markers, higher bone formation markers, less muscle mass loss, and a reduction in MAT compared to a lifestyle intervention resulting in a comparable amount of weight loss, Healthy Habits for Life (HHL), in 40 otherwise healthy adults with obesity. The current proposal is a pilot study with two aims: Aim 1 investigates the effects of liraglutide on bone metabolism markers and MAT compared to an intensive lifestyle intervention for weight loss, while Aim 2 investigates the effects of liraglutide on muscle mass and strength compared to an intensive lifestyle intervention for weight loss. The proposed protocol builds on Dr. Melanie Schorr Haines’s K23 project and growing area of expertise in the endocrine determinants of body composition, with a focus on muscle, and their contribution to cardiometabolic disease and skeletal integrity. This pilot study will provide critical preliminary data for an R01 proposal to conduct a prospective, randomized, controlled trial to determine whether GLP-1 RAs result in pre...