Comparison of the characteristics of non-alcoholic fatty liver disease in C57BL/6J-Lepr(em1hwl)/Korl and C57BLKS/J-Lepr(db)/J mice.

The Lepr gene encodes a receptor for leptin, a hormone instrumental in the regulation of appetite and metabolism. Mutations in the Lepr gene impair leptin signaling, leading to metabolic dysfunctions and facilitating the development of non-alcoholic fatty liver disease (NAFLD). In this study, we compared the NAFLD-associated phenotypes of two mutant strains of mice, C57BL/6J-Lepr(em1hwl)/Korl (Lepr(em1hwl)) and C57BLKS/J-Lepr(db)/J (Lepr(db/db)), carrying different alleles of the Lepr gene. Although both Lepr(em1hwl) and Lepr(db/db) mice were characterized by similar obesity phenotypes, leptin resistance, insulin resistance, and glucose intolerance, comparatively, Lepr(em1hwl) mice were found to have relatively more severe hepatic steatosis, along with the upregulated expression of enzymes associated with lipogenesis and triglyceride synthesis, and, notably, the histological characteristics of steatohepatitis were observed only in these mice. In addition, compared with the Lepr(db/db) mice, Lepr(em1hwl) mice developed hepatic fibrosis characterized by elevated levels of collagen deposition and expression of profibrotic factors. Moreover, we detected elevated levels of pro-inflammatory mediators and increases in classically activated macrophage markers in the serum and liver, respectively, of Lepr(em1hwl) mice. These findings highlight the distinct NAFLD-associated phenotypic differences between Lepr(em1hwl) and Lepr(db/db) mice, and thereby indicate that Lepr(em1hwl) mice could serve as a valuable model for studying NAFLD, including steatohepatitis and fibrosis.