PubMed1 Apr 2026International journal of obesity (2005)● 6/10i Efficacy of GLP-1 analog peptides, semaglutide, tirzepatide, and retatrutide on MC4R deficient obesity and their comparison.
Hitaka K, Sugawara T, Matsumoto M, Nio Y
Tirzepatide achieved 31.6% weight reduction versus 19.7% for semaglutide and 24.1% for retatrutide in MC4R knockout mice, a model of severe genetic obesity. Preclinical study, 21-day treatment duration in mice deficient in melanocortin pathways. This provides the first head-to-head comparison of major GLP-1 therapies in severe genetic obesity, suggesting these agents work through MC4R-independent mechanisms.
Strategic Signal
This data provides Lilly with preclinical evidence to explore tirzepatide for rare genetic obesity indications like MC4R deficiency, potentially opening orphan drug pathways with accelerated approval timelines and premium pricing. The superior efficacy versus semaglutide in this model strengthens Lilly's competitive positioning for specialized obesity populations. FDA's breakthrough therapy designation becomes more accessible for genetic obesity, following precedents like Rhythm Pharmaceuticals' setmelanotide approval for POMC deficiency.
Original Abstract
INTRODUCTION: Melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor expressed in the hypothalamus, playing a key role in regulating feeding behavior and energy homeostasis. MC4R is integral to the POMC-MC4R and leptin-MC4R pathways, which control food intake and body weight. Mutations in the POMC gene lead to severe early-onset obesity and increased food consumption. Recently, glucagon-like peptide-1 (GLP-1) analogs, including semaglutide, tirzepatide, and retatrutide, have been explored as potential anti-obesity therapies. METHODS: This study aimed to assess and compare the efficacy of these GLP-1 analogs in MC4R knockout (KO) mice, which are deficient in the POMC-MC4R pathway. GLP-1 analogs were administered for 21 days to MC4R KO mice and compared their efficacy. RESULTS: The percentage of body weight reduction was 19.7 ± 4.1% for semaglutide, 31.6 ± 7.6% for tirzepatide, and 24.1 ± 5.8% for retatrutide. Body composition analysis, including fat and lean mass, was performed using the Echo-MRI system, revealing significant suppression of both fat and lean mass by all three GLP-1 analogs. Furthermore, GLP-1 analogs improved plasma insulin levels, HOMA-IR, cholesterol levels, and markers of liver damage (AST and ALT), as well as reduced liver hypertrophy. While GLP-1 analogs suppressed genes related to fatty acid synthesis, they had no significant effect on inflammation-related gene expressions. Additionally, GLP-1 analogs reduced energy expenditure, with only tirzepatide showing a significant decrease in the respiratory quotient (RQ) in MC4R KO mice. CONCLUSION: Our findings demonstrate that all three GLP-1 analogs, semaglutide, tirzepatide, and retatrutide, exhibit significant anti-obesity effects in MC4R KO mice. These results suggest that GLP-1 analogs may provide an effective treatment option for patients with MC4R-POMC pathway deficiencies. Moreover, the efficacy of these drugs in MC4R KO mice aligns with clinical studies, indicating that MC4R KO mice serve as a reliable animal model for obesity research.