Targeting peroxisome proliferator-activated receptor proteasomal degradation by magnolol is a potential avenue for adipogenesis-mediated metabolic homeostasis

ObjectiveAdipogenesis has been recognized as an attractive avenue for maintaining systemic homeostasis, with peroxisome proliferator-activated receptor gamma (PPAR gamma) showing predominant roles in this process. This study aims to identify promising drug candidates by targeting PPAR gamma for adipogenesis-based metabolic homeostasis and to clarify the detailed mechanisms. MethodsMolecular events contributing to adipogenesis were screened, which identified PPAR gamma as having the predominant role. Promising agents of adipogenesis agonism were screened using a PPAR gamma-based luciferase reporter assay. The functional capacity and molecular mechanisms of magnolol were intensively examined using 3T3-L1 preadipocytes and dietary models. ResultsThis study found that F-box only protein 9 (FBXO9)-mediated lysine 11 (K11)-linked ubiquitination and proteasomal degradation of PPAR gamma are critically required during adipogenesis and systemic homeostasis. Notably, magnolol was identified as a potent adipogenesis activator by stabilizing PPAR gamma. The pharmacological mechanisms investigations clarified that magnolol directly binds to PPAR gamma and markedly interrupts its interaction with FBXO9, leading to a decline in K11-linked ubiquitination and proteasomal degradation of PPAR gamma. Clinically important, magnolol treatment significantly facilitates adipogenesis in vitro and in vivo. ConclusionsThe downregulation of K11-linked ubiquitination of PPAR gamma caused by FBOX9 is essentially required for adipogenesis, while targeting PPAR gamma-FBXO9 interaction provides a new avenue for the therapy of adipogenesis-related metabolic disorder.