Molecular mechanism of MAFB transcriptional activation of PPARD in regulating adipose browning and protecting against vascular endothelial cell injury

Background: Adipose browning in perivascular adipose tissue (PVAT) confers vascular protection, yet its molecular regulation remains poorly defined. The transcription factor MAFB has been implicated in this process, but its downstream targets are unclear.

Methods: Bioinformatics analyses were performed to identify browning-related targets of MAFB, highlighting PPARD as a candidate. 3T3-L1 adipocytes were used to investigate MAFB's role in browning. ChIP and luciferase assays assessed MAFB binding and transcriptional activation. Functional consequences were examined via PPARD knockdown and HCAECs co-culture.

Results: MAFB overexpression enhanced UCP1, PPARGC1α, PRDM16, and CIDEA expression, mitochondrial content, oxygen consumption, and Adiponectin secretion, while reducing ASC1 in adipocytes. MAFB directly bound to and activated the PPARD promoter. PPARD knockdown diminished MAFB-induced browning. Conditioned medium from brown adipocytes protected HCAECs and primary mouse vascular endothelial cellsmore effectively than white adipocyte medium. Modulating the MAFB-PPARD axis in adipocytes significantly influences endothelial cell viability, Apoptosis, and inflammatory responses.

Conclusion: MAFB promotes adipocyte browning via direct transcriptional activation of PPARD, contributing to endothelial protection. The MAFB-PPARD axis may offer a novel therapeutic target for vascular and metabolic diseases.