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.

BackgroundPathological cardiac hypertrophy is commonly resulted from sustained pressure overload and/or metabolic disorder and eventually leads to heart failure, lacking specific drugs in clinic. Here, we aimed to identify promising anti-hypertrophic drug(s) for heart failure and related metabolic disorders by using a luciferase reporter-based high-throughput screening.MethodsA screen of the FDA-approved compounds based on luciferase reporter was performed, with identified luteolin as a promising anti-hypertrophic drug. We systematically examined the therapeutic efficacy of luteolin on cardiac hypertrophy and heart failure in vitro and in vivo models. Transcriptome examination was performed to probe the molecular mechanisms of luteolin.ResultsAmong 2,570 compounds in the library, luteolin emerged as the most robust candidate against cardiomyocyte hypertrophy. Luteolin dose-dependently blocked phenylephrine-induced cardiomyocyte hypertrophy and showed extensive cardioprotective roles in cardiomyocytes as evidenced by transcriptomics. More importantly, gastric administration of luteolin effectively ameliorated pathological cardiac hypertrophy, fibrosis, metabolic disorder, and heart failure in mice. Cross analysis of large-scale transcriptomics and drug-target interacting investigations indicated that peroxisome proliferator activated receptor γ (PPARγ) was the direct target of luteolin in the setting of pathological cardiac hypertrophy and metabolic disorders. Luteolin can directly interact with PPARγ to inhibit its ubiquitination and subsequent proteasomal degradation. Furthermore, PPARγ inhibitor and PPARγ knockdown both prevented the protective effect of luteolin against phenylephrine-induced cardiomyocyte hypertrophy in vitro.ConclusionOur data clearly supported that luteolin is a promising therapeutic compound for pathological cardiac hypertrophy and heart failure by directly targeting ubiquitin-proteasomal degradation of PPARγ and the related metabolic homeostasis.

Background Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms. Methods A drug repositioning strategy was used to screen an FDA-approved drug library with approximately 3000 compounds in an in vitro hepatocyte model of lipid accumulation, with honokiol identified as an effective anti-NAFLD candidate. We systematically examined the therapeutic effect of honokiol in NAFLD and metabolic syndrome in multiple in vitro and in vivo models. Transcriptomic examination and biotin-streptavidin binding assays were used to explore the underlying molecular mechanisms, confirmed by rescue experiments. Results Honokiol significantly inhibited metabolic syndrome and NAFLD progression as evidenced by improved hepatic steatosis, liver fibrosis, adipose inflammation, and insulin resistance. Mechanistically, the beneficial effects of honokiol were largely through AMPK activation. Rather than acting on the classical upstream regulators of AMPK, honokiol directly bound to the AMPKγ1 subunit to robustly activate AMPK signaling. Mutation of honokiol-binding sites of AMPKγ1 largely abolished the protective capacity of honokiol against NAFLD. Conclusion These findings clearly demonstrate the beneficial effects of honokiol in multiple models and reveal a previously unappreciated signaling mechanism of honokiol in NAFLD and metabolic syndrome. This study also provides new insights into metabolic disease treatment by targeting AMPKγ1 subunit-mediated signaling activation.

BackgroundThe purpose of our study was to study the composition and content of the feline plasma metabolome revealing the critical metabolites and metabolic pathways associated with age during growth and development.MethodsBlood samples were collected from juvenile and adult groups for blood routine tests and serum biochemistry tests. Non‐targeted metabolomics analyses of plasma were also performed to investigate changes in metabolites and metabolic pathways.ResultsIn this study, we found that the red blood cell counts, liver function indexes (albumin and gamma‐glutamyl transpeptidase), and the concentration of triglyceride and glucose changed significant with growth and development. The metabolomics results revealed that 1427 metabolites were identified in the plasma of young and adult cats. Most of these metabolites belong to major classes of lipids and lipid‐like molecules. The most obvious age‐related metabolites include reduced levels of chenodeoxycholate, taurocholate, cholate, and taurochenodeoxycholate but increased levels of L‐cysteine and taurocyamine in the adult cat's serum. These metabolites are mainly involved in the primary bile acid biosynthesis pathway, the bile secretion pathway, and the taurine and hypotaurine metabolism pathway.ConclusionThis study revealed many age‐related metabolite alterations in the feline plasma. These age‐varying metabolites, especially in the bile acid biosynthesis and secretion metabolism pathways, indicate that the regulation of these pathways is involved in the growth and development of cats. This study promotes our understanding of the mechanism of feline growth and provides new insights into nutrition and medicine for cats of different ages.