Autor: |
Diep DTV; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea., Hong K; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea., Khun T; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea., Zheng M; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea., Ul-Haq A; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea., Jun HS; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea.; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Republic of Korea.; Gachon Medical Research Institute, Gil Hospital, Incheon, 21565, Republic of Korea., Kim YB; Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States. ykim2@bidmc.harvard.edu.; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, 21999, Republic of Korea. ykim2@bidmc.harvard.edu., Chun KH; Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea. khchun@gachon.ac.kr. |
Abstrakt: |
Adipose tissue is a specialized organ that synthesizes and stores fat. During adipogenesis, Rho and Rho-associated kinase (ROCK) 2 are inactivated, which enhances the expression of pro-adipogenic genes and induces the loss of actin stress fibers. Furthermore, pan ROCK inhibitors enhance adipogenesis in 3T3-L1 cells. Here, we show that KD025 (formerly known as SLx-2119), a ROCK2-specific inhibitor, suppresses adipogenesis in 3T3-L1 cells partially through a ROCK2-independent mechanism. KD025 downregulated the expression of key adipogenic transcription factors PPARγ and C/EBPα during adipogenesis in addition to lipogenic factors FABP4 and Glut4. Interestingly, adipogenesis was blocked by KD025 during days 1~3 of differentiation; after differentiation terminated, lipid accumulation was unaffected. Clonal expansion occurred normally in KD025-treated cells. These results suggest that KD025 could function during the intermediate stage after clonal expansion. Data from depletion of ROCKs showed that KD025 suppressed cell differentiation partially independent of ROCK's activity. Furthermore, no further loss of actin stress fibers emerged in KD025-treated cells during and after differentiation compared to control cells. These results indicate that in contrast to the pro-adipogenic effect of pan-inhibitors, KD025 suppresses adipogenesis in 3T3-L1 cells by regulating key pro-adipogenic factors. This outcome further implies that KD025 could be a potential anti-adipogenic/obesity agent. |