Differences Between Therapeutic Mechanisms of Resmetirom and Semaglutide Against MASH in Western diet-fed MC4R Knockout Mice

Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to metabolic dysfunction-associated steatohepatitis (MASH), which is closely linked to obesity and insulin resistance. Resmetirom, the first approved drug for MASH, and semaglutide, a GLP-1 receptor agonist, have shown therapeutic effects in clinical studies. This study aimed to compare their mechanisms in Western diet (WD)-fed melanocortin 4 receptor-knockout (MC4R-KO) mice, a model that mimics human MASH pathology. MC4R-KO mice fed a WD for 6 weeks were treated with resmetirom or semaglutide for 7 weeks. WD-fed MC4R-KO mice showed increased liver weight and plasma aspartate aminotransferase and alanine transaminase levels. Both the resmetirom and semaglutide treatments substantially improved these parameters. Although resmetirom and semaglutide improved liver hydroxyproline deposition and fat mass, semaglutide markedly suppressed lean mass. Moreover, in terms of energy expenditure, resmetirom enhanced oxygen consumption, whereas semaglutide reduced it. In conclusion, the different mechanisms of resmetirom and semaglutide against MASH were revealed. Similar to clinical evidence, semaglutide treatment, unlike resmetirom, may cause muscle mass reduction due to food intake suppression. To our knowledge, this study is the first to simultaneously compare the effects of resmetirom and semaglutide on MASH phenotypes and reveal their mechanism of action using WD-fed MC4R-KO mice.