Magnolol inhibits appetite and causes visceral fat loss through GDF-15 by activating transcription factor 4-CCAAT enhancer binding protein γ-mediated endoplasmic reticulum stress responses

Magnolol is a chemical compound extracted from Magnolia officinalis, and is believed to be effective in addressing metabolic dysfunction and cardiovascular diseases. The biological activities of magnolol include anti-inflammatory, anti-oxidant, anti-coagulant, and anti-diabetic effects. Growth/differentiation factor-15 (GDF-15) is a member of the transforming growth factor β superfamily and is expected to be considered as a therapeutic target for metabolic disorders. The present study examined the impact of magnolol on GDF-15 production and the mechanism that underlies it. We studied the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo, and determined if endoplasmic reticulum (ER) stress signaling is involved in the process. Luciferase reporter assay, chromatin immunoprecipitation and in vitro DNA binding assay were used to examine the regulation of GDF-15 by activating transcription factor 4 (ATF4), CCAAT enhancer binding protein γ (CEBPG), and CCCTC-binding factor (CTCF). The effect of magnolol and ATF4 on the activity of a putative enhancer located in intron of the GDF-15 gene was investigated. This study also examined the influence of single nucleotide polymorphism (SNP) on magnolol and ATF4-induced transcription activity. The results showed that magnolol triggers GDF-15 production in endothelial cells, HepG2 and Hep3B cell lines and primary mouse hepatocytes. The cooperative ATF4 and CEBPG bound upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of GDF-15 gene. SNP alleles have an impact on the magnolol and ATF4-induced transcription activity of GDF-15. In high-fat diet ApoE^-/- mice, administration of magnolol induces GDF-15 production and suppresses appetite partially through GDF-15. The present findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity. Magnolol is a potential drug for the treatments for metabolic disorders.