OR09-07 Dynamic Proteomic Profiling in a 5-week Crossover Trial of Liraglutide in Obesity Reveals Weight-Dependent Myostatin Downregulation and Multi-Pathway Effects Beyond Weight Reduction

Abstract Disclosure: K. Stefanakis: None. P. Veeragandham: None. V. Gutierrez de Pineres: None. C.S. Mantzoros: Novo Nordisk. The recent FDA approval of generic Liraglutide necessitates a better understanding of its downstream molecular mechanisms to develop obesity treatments that reduce adiposity while preserving lean body mass, key factors in mitigating sarcopenia associated with GLP-1 agonists. In a 5-week crossover randomized, double-blind, placebo-controlled trial, 20 participants with obesity received Liraglutide (3.0 mg/day) or placebo in random sequence, separated by a minimum 3-week washout period. The SomaScan v4.1 platform was used to quantify approximately 7,000 proteins across serum and plasma samples with robust quality controls. Longitudinal proteomic changes were assessed using FDR-corrected pre-to-post comparisons and adjusted mixed models, whereas enrichment analyses were performed using gene and disease ontology, and data from deCODE GWAS. Liraglutide treatment resulted in a significant weight reduction (-2.99 kg placebo-subtracted) and improved glucose and lipid profiles. Out of 6,249 common proteins analyzed, 338 proteins had a significant Time*Treatment interaction, of which Liraglutide significantly upregulated 84 and downregulated 104 proteins, whereas placebo had minimal effects. Specifically, Liraglutide increased exocrine pancreatic proteins (e.g., PNLIPRP1, PRSS2, CTRB2) and fatty acid–binding proteins (e.g., FABP4), and decreased proteins related to fibrosis, inflammation, collagen deposition, and neural development - potentially related to known effects of Liraglutide on appetite regulation and hypothalamic centers. Most proteomic changes were independent of weight and glucose; however, myostatin (MSTN), a negative regulator of muscle growth, was downregulated in a weight-dependent manner, and its inhibitor WFIKKN2, alongside TGF-β receptor BMPR1a were upregulated, suggesting a compensatory mechanism to preserve lean mass during early weight loss. ELISA validation confirmed the proteomic measurements for MSTN (r=0.78, p<10-14). Pathway enrichment analyses indicated reductions in fibrosis and inflammatory processes, and in pathways associated with cardiovascular, renal, and liver diseases, alongside differential regulation of apoptosis, and enhancements in digestion, lipid metabolism, and humoral immunity. Secondary analyses identified distinct proteomic signatures in seven participants who lost more than 3% of their baseline weight, involving neurotransmitter and insulin-regulating proteins. Unlike longer-term weight loss studies, these results capture early molecular adaptations, with the myostatin axis emerging as a target for combination therapies to minimize lean tissue loss. These insights are critical to better understand the mechanisms of weight loss and to optimize the development of novel compounds aimed towards myostatin antagonism to concomitantly lose fat and preserve lean body mass and metabolic health. Presentation: Saturday, July 12, 2025