In adults with obesity, 5-10% weight loss improves cardiometabolic risk, including insulin sensitivity, but not all components of weight loss are equally beneficial. Individuals would preferentially lose fat mass, particularly visceral fat, a major cardiometabolic risk factor. However, 20-40% of weight lost through diet, pharmacotherapy, or surgery in adults with obesity is lean mass, which mitigates improvements in insulin sensitivity—consistent with the fact that skeletal muscle is responsible for most insulin-mediated glucose disposal—and contributes to weight regain by reducing resting energy expenditure. Loss of bone mass is another unintentional consequence of weight loss, which increases the risk of osteoporosis and fractures. Therefore, optimum weight loss strategies should preserve muscle and bone mass. If a lifestyle intervention (diet and exercise) does not achieve weight loss goals, options include pharmacotherapy such as the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 receptor agonist (GLP-1 RA), tirzepatide. Although the effects of tirzepatide on bone are not known, the GLP-1 RA, semaglutide, suppresses bone resorption and increases bone formation in adults with obesity and stable weight, and preclinical data suggest that GIP inhibits bone resorption and improves osteoblast survival, suggesting tirzepatide may not result in bone loss. Bimagrumab, an investigational new drug for obesity that inhibits the activin type II receptor (ActRII), may be anabolic to muscle and bone. Blockade of the myostatin/activin-ActRII pathway increases muscle mass, reduces fat mass, and improves insulin sensitivity while increasing bone formation, reducing bone resorption, and increasing bone mass in rodents. Early clinical data in adults with obesity and type 2 diabetes suggest that bimagrumab reduces visceral fat mass and increases lean mass. Although just one dose of bimagrumab increases whole body insulin sensitivity, it is unclear whether bimagrumab improves skeletal muscle insulin sensitivity. One dose of another ActRII inhibitor increases bone formation and decreases bone resorption, but longer-term effects on bone are unknown. We hypothesize that in a double-blind, placebo-controlled trial of 63 adults with obesity randomized in 1:1:1 of tirzepatide 15mg SQ qweek + bimagrumab 300mg SQ qweek, tirzepatide 15mg SQ week, or bimagrumab 300mg SQ qweek, tirzepatide + bimagrumab will result in metabolic improvements in muscle (Aim 1), visceral fat (Aim 2), and bone (Aim 3) vs. tirzepatide or bimagrumab over 52 weeks as an adjunct to a lifestyle intervention for weight loss. To investigate whether tirzepatide + bimagrumab improves tissue-specific insulin sensitivity, 27 subjects will undergo hyperinsulinemic–euglycemic clamps at baseline and Week 52. Understanding the effects of tirzepatide + bimagrumab vs. tirzepatide or bimagrumab will determine whether ActRII inhibition combined with GIP and GLP-1 RA reduces metabolic...