Introduction and Objective: Hepatic stellate cells (HSCs) play a key role in developing insulin resistance. While Rho-kinase 1 (ROCK1) activation in hepatocytes promotes obesity-induced insulin resistance, the physiological role of ROCK1 in HSCs remains unclear. This study investigated the importance of ROCK1 in HSCs in the context of obesity-related metabolic dysfunction.Methods: Mice lacking ROCK1 in HSCs (Lrat-Cre; ROCK1 loxP/loxP ) were fed a high-fat diet (HFD) for 22 weeks. Metabolic assessments included glucose and insulin tolerance tests, serum insulin, and lipids profiles. Gene expression of key molecules involved in hepatic inflammation, fibrosis, and muscle function were also determined.Results: Hepatic ROCK1 expression increased notably in HFD-fed mice. ROCK1 deficiency in HSCs prevented HFD-induced obesity, resulting from decreased lean mass but not fat mass. Lrat-Cre; ROCK1 loxP/loxP mice were insulin sensitive, evidenced by a significant decrease in blood glucose levels after insulin injection, while glucose tolerance remained normal. Serum insulin was decreased, but blood glucose was unaltered. Hepatic TG content increased with the upregulated lipogenic genes (ACC and ChREBP) in Lrat-Cre; ROCK1 loxP/loxP mice, but serum lipid profiles were unchanged. No changes in hepatic inflammatory or fibrosis markers were observed. Interestingly, despite reduced lean mass, skeletal muscle showed increased expression of genes linked to differentiation and functionality (Myl2, Myl4, Myog, IGFBP5, Desmin, Mef2c) and decreased expression of atrophy markers (MuRF1, atrogin-1), likely contributing to the insulin-sensitive phenotype.Conclusion: These data suggest that ROCK1 in HSCs is a key mediator that regulates insulin sensitivity and muscle functionality during overnutrition, highlighting ROCK1’s significance in HSCs-muscle communication. Identifying HSC-derived factors that affect muscle function is under investigation.
K. Rodrigues: None. L. Zhang: None. J. Young: None. M. Lee: None. Y. Lim: None. W. Yang: None. P. Hirsova: None. Y. Kim: None.
American Diabetes Association (1-25-PDF-49); RO1DK129946
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