Semaglutide Improves Liver Steatosis and De Novo Lipogenesis Markers in Obese and Type-2-Diabetic Mice with Metabolic-Dysfunction-Associated Steatotic Liver Disease.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Diabetes Mellitus, Experimental*/metabolism ; Fatty Liver*/metabolism ; Diabetes Mellitus, Type 2*/metabolism ; Non-alcoholic Fatty Liver Disease*/metabolism ; Glucagon-Like Peptides*; Humans ; Animals ; Mice ; Lipogenesis ; Leptin/metabolism ; Obesity/metabolism ; Liver/metabolism ; Body Weight ; Triglycerides/metabolism ; Mice, Obese

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent clinical condition associated with elevated morbidity and mortality rates. Patients with MASLD treated with semaglutide, a glucagon-like peptide-1 receptor agonist, demonstrate improvement in terms of liver damage. However, the mechanisms underlaying this beneficial effect are not yet fully elucidated. We investigated the efficacy of semaglutide in halting MASLD progression using a genetic mouse model of diabesity. Leptin-receptor-deficient mice with obesity and diabetes (BKS db/db) were either untreated or administered with semaglutide for 11 weeks. Changes in food and water intake, body weight and glycemia were monitored throughout the study. Body fat composition was assessed by dual-energy X-ray absorptiometry. Upon sacrifice, serum biochemical parameters, liver morphology, lipidomic profile and liver-lipid-related pathways were evaluated. The semaglutide-treated mice exhibited lower levels of glycemia, body weight, serum markers of liver dysfunction and total and percentage of fat mass compared to untreated db/db mice without a significant reduction in food intake. Histologically, semaglutide reduced hepatic steatosis, hepatocellular ballooning and intrahepatic triglycerides. Furthermore, the treatment ameliorated the hepatic expression of de novo lipogenesis markers and modified lipid composition by increasing the amount of polyunsaturated fatty acids. The administration of semaglutide to leptin-receptor-deficient, hyperphagic and diabetic mice resulted in the amelioration of MASLD, likely independently of daily caloric intake, suggesting a direct effect of semaglutide on the liver through modulation of the lipid profile.

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PI20/00375 Instituto de Salud Carlos III; PI23/00119 Instituto de Salud Carlos III

Keywords: GLP1 receptor agonists; diabetes; insulin resistance; obesity; semaglutide; steatosis

53AXN4NNHX (semaglutide)
0 (Leptin)
0 (Triglycerides)
62340-29-8 (Glucagon-Like Peptides)

Date Created: 20240313 Date Completed: 20240314 Latest Revision: 20240315

20240315

PMC10932050

10.3390/ijms25052961

38474208