The impact of leptin receptor (LepR) mutation on the development of MASLD in a murine model.

Genes play an important role in regulating insulin signaling, adipokines, oxidative stress, lipid metabolism, and inflammation in susceptibility and progression of Metabolic dysfunction-associated steatotic liver disease (MASLD). Among various genes, the LepR gene influences insulin sensitivity and controls lipid metabolism, contributing to the development of MASLD. Our previous study reported that a novel congenic mouse (WSB.db) with a LepR mutation exhibited resistance to MASLD. To further evaluate this strain for resistance, we fed this new mouse strain with LepR mutation and B6.db mice, the mouse model of metabolic disease with a high-fat diet as a second hit for 12 weeks and evaluated the pathophysiology, serum biochemistry, Quantitative real-time polymerase chain reaction (qPCR) to determine the expression of specific genes involved in the development of fatty changes in the liver and hepatic transcriptome signatures in liver tissue. In contrast to db/db (B6.db) mice, which exhibited all the pathological hallmarks for MASLD, the LepR mutant congenic strain was still resistant to developing liver steatosis. Transcriptome analysis with KEGG PATHWAY: hsa04932 revealed significant upregulation of AMPKγ3 and MApk10 (JNK3) in WSB.db mice, suggesting that congenic mice with the LepR mutation are resistant to MASLD without the liver pathology to effect. These results propose that the LepR mutation has a different impact on liver pathology depending on genetic background, indicating upregulation of specific genes in the development of MASLD. This study will facilitate the identification of therapeutic targets against MASLD with LepR mutation.