TUG-891-mediated FFAR4 activation attenuates vascular remodeling via suppression of aberrant browning and lipolysis in perivascular adipose tissue.

BACKGROUND: Free fatty acid receptor 4 (FFAR4) activation modulates adipogenesis, but this pathway has not been explored in the context of perivascular adipose tissue (PVAT) dysfunction and vascular remodeling. METHODS: Adipose tissue-specific FFAR4 knockout (Adipo-Ffar4-/-, Adipo-KO) mice were generated by crossing Adipoq-Cre and Ffar4flox/flox (WT) mice. FeCl₃-induced PVAT injury model in abdominal aorta was established. TUG-891 (20 mg/kg/day, i.p.) was administered for 4 weeks. In vitro, FeCl₃-conditioned medium was prepared with mouse PVAT explants. Proliferation and migration of vascular smooth muscle cells (VSMCs) cultured with conditioned medium were assessed. RESULTS: FFAR4 was particularly upregulated in abdominal aortic PVAT in response to high-fat diet. TUG-891-mediated FFAR4 activation in PVAT alleviated abdominal aortic dysfunction and hyperplasia in WT mice. TUG-891 also prohibited aberrant lipolysis and browning, as evidenced by lower serum FFA levels and downregulated UCP1 expression, in a FFAR4-dependent manner. Expression of pro-remodeling genes (CCL2, MMP9, SPP1) in damaged PVAT was reduced by TUG-891. These protective effects were absent in Adipo-KO mice. In vitro, conditioned medium from FeCl₃-primed PVAT promoted VSMC proliferation and migration, which was attenuated by TUG-891 in the presence of FFAR4. Free fatty acids also enhanced VSMC proliferation and migration. These effects were abolished when using PVAT or cells from Adipo-KO mice. CONCLUSION: These results indicate that TUG-891 mitigates vascular hyperplasia and remodeling by activating FFAR4 in PVAT, reducing lipolysis and suppressing aberrant adipocyte browning. Targeting PVAT FFAR4 signaling may represent a promising therapeutic strategy for vascular diseases.