Introduction and Objective: Acyl-CoA synthetase long-chain family member 1 (ACSL1) is activated in macrophages by palmitate, driving foam cell formation through the CD36/FABP4/PPARδ axis. Our prior research showed that inhibiting ACSL1 reduces inflammation and alters lipid uptake, suggesting it as a therapeutic target. Here, we examined whether oral Triacsin C, a small-molecule ACSL inhibitor, can reduce weight gain in mice.Methods: Male mice were fed a high-fat diet (HFD) for 14 weeks with or without daily oral Triacsin C. Additional groups received HFD for 8 weeks, followed by either continued HFD or a switch to chow, with Triacsin C administration initiated or stopped to assess efficacy and durability. We measured body weight, subcutaneous and visceral fat, liver histopathology, inflammatory cell subsets (CD11c+CX3CL1+), and intestinal lipid absorption.Results: Triacsin C-treated mice on HFD gained significantly less weight, approaching chow-fed controls, and showed decreased subcutaneous and visceral fat. Although liver weight was unchanged, liver steatosis and macrophage infiltration were markedly reduced. Triacsin C also prevented the rise in inflammatory CD11c+CX3CL1+ cells and lowered intestinal lipid uptake. In established obesity, Triacsin C alone prompted weight loss, with even greater effects when combined with a chow switch. Upon drug withdrawal, weight rebounded only if mice remained on HFD, whereas those switched to chow retained improved weight profiles.Conclusion: Triacsin C-mediated ACSL1 inhibition offers a promising strategy for reducing weight gain and improving metabolic health. Further clinical studies are needed to assess its safety and translational potential in obesity management.
F. Alrashed: None. H. AlSaeed: None. T.K. Jacob: None. R.S. Thomas: None. S. Shenouda: None. S.P. Kochumon: None. F. Almulla: None. R. Ahmad: None.
Kuwait foundation for the advancement of science (KFAS) Grant number: RA-CB 2020-004
Source link
Leave a Reply