GLP-1 Analog Peptides Show Anti-Obesity Efficacy for MC4R Deficiencies

A new preclinical study confirms that three glucagon-like peptide-1 (GLP-1) analog peptides produce significant weight loss in specific models. In view of this, researchers tested semaglutide, tirzepatide, and retatrutide in subjects lacking the melanocortin 4 receptor (MC4R). To be precise, these drugs remain effective even when the POMC-MC4R pathway is completely disrupted. Along with this, the findings appeared in the International Journal of Obesity to address rare genetic disorders.

MC4R is a receptor in the hypothalamus that governs feeding behavior and energy homeostasis. Furthermore, deficiencies in this pathway cause severe early-onset obesity and metabolic dysregulation. For this reason, patients often experience increased food intake and significant challenges with weight management. In light of this, setmelanotide is currently the only approved therapy for certain MC4R-related conditions.

The existing therapy offers a limited 5.2% weight reduction for patients with Bardet-Biedl syndrome. On top of that, modern GLP-1 analogs like Wegovy and Mounjaro show much higher efficacy. Particularly, researchers at Axcelead Drug Discovery Partners administered daily subcutaneous doses for 21 days. Consequently, all three agents produced statistically significant body weight reductions in the study models.

Semaglutide achieved a 19.7 ± 4.1% reduction while retatrutide reached 24.1 ± 5.8%. As a result, tirzepatide led the group with a 31.6 ± 7.6% decrease in weight. Moreover, tirzepatide reduced cumulative food intake most aggressively at 29.7 ± 9.0 g. In addition, semaglutide and retatrutide resulted in intake levels of 52.2 ± 7.1 g and 43.9 ± 9.0 g.

Weight Loss and Metabolic Outcomes of GLP-1 Analogs in MC4R-Deficient Models

Drug	Weight Reduction	Cumulative Food Intake	Key Metabolic Effects
Semaglutide	19.7 ± 4.1%	52.2 ± 7.1 g	Reduced insulin, AST/ALT, and fat mass
Tirzepatide	31.6 ± 7.6%	29.7 ± 9.0 g	Greatest weight loss, improved lipids, ↓ RQ (fat oxidation)
Retatrutide	24.1 ± 5.8%	43.9 ± 9.0 g	Reduced insulin, liver enzymes, and fat mass

Body composition analysis using Echo-MRI and X-ray CT revealed a suppression of fat and lean mass. Subsequently, visceral fat showed the most pronounced reduction during the three weeks. Therefore, the treatment correlated strongly with a decrease in total fat mass. Accordingly, all three GLP-1 analogs also improved liver and cardiac hypertrophy in the subjects.

Plasma biochemistry data further strengthened the metabolic case for these obesity therapies. Hence, all three agents significantly reduced insulin levels and HOMA-IR scores. Notably, the medications lowered aspartate aminotransferase (AST) and alanine transaminase (ALT) levels. Similarly, tirzepatide produced the most robust improvements in triglycerides and total cholesterol.

These cardiometabolic benefits align with the dual agonist activity of tirzepatide. Likewise, the drug acts on both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. Meanwhile, gene expression analysis showed that all three analogs downregulated hepatic lipid synthesis genes. Indeed, these genes included fatty acid synthase (FASN) and stearoyl-CoA desaturase-1 (SCD-1).

None of the agents significantly suppressed pro-inflammatory gene expression in the liver. Nonetheless, the observed metabolic improvements appear to stem from lipid and glucose modulation. Thus, the drugs focus on metabolic pathways rather than direct anti-inflammatory activity. Despite this, the anti-obesity response remains powerful even without intact MC4R signaling.

GLP-1 analogs exert anorectic effects by acting upstream of the MC4R receptor. Given this, the downstream blockade does not eliminate the clinical efficacy of the peptides. Building on this, the drugs engage central and peripheral pathways beyond melanocortin signaling. With this in mind, the agents reduced the metabolic rate in both light and dark phases.

Only tirzepatide produced a significant decrease in the respiratory quotient (RQ). In response to this, the data indicate a pronounced shift toward fat oxidation. What is more, all three analogs reduced lean mass during the trial. Beyond this, researchers expressed concerns regarding sarcopenia risk during long-term weight loss.

The authors acknowledge that the study used a short three-week evaluation period. Nevertheless, the MC4R KO model showed strong concordance with clinical trial data. In addition, this model may serve as a reliable platform for evaluating Prader-Willi syndrome. Consequently, these findings support the use of GLP-1 therapy for genetic obesity disorders.

References

1. Hitaka, K., Sugawara, T., Matsumoto, M., & Nio, Y. (2026). Efficacy of GLP-1 analog peptides, semaglutide, tirzepatide, and retatrutide on MC4R-deficient obesity and their comparison. International Journal of Obesity. https://doi.org/10.1038/s41366-026-02025-2
2. Jastrzębska-Mierzyńska, M., Łukasiewicz, A., & Ostrowska, L. (2023). The effects of semaglutide on body composition in patients with obesity. Nutrients, 15(18), 3956. https://doi.org/10.3390/nu15183956
3. Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., et al. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387, 205–216. https://doi.org/10.1056/NEJMoa2206038
4. Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., et al. (2023). Triple-hormone-receptor agonist retatrutide for obesity: A phase 2 trial. New England Journal of Medicine, 389, 514–526. https://doi.org/10.1056/NEJMoa2301972