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

Abstract

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

Transcriptome profiling of cerebrospinal fluid in Alzheimer’s Disease reveals molecular dysregulations associated with disease

“…In contrast, CNR1 and GPD2 were the most downregulated genes in moderate dementia compared to mild dementia (Wilcoxon rank-sum test) (Figure 4C). Of note, both FBXO9 and SEZ6L2 have been shown to be involved in proteostasis (38, 39), a known feature of AD (40). In addition, SEZ6L2 has been shown to have implications in neuronal and especially motor function development (41, 42).…”