Melatonin alleviates endoplasmic reticulum stress and its mediated inflammation in adipocytes via the PER1/ATF6 signal

Obesity is a major global health challenge closely associated with various metabolic diseases. A deeper understanding of the mechanisms underlying obesity, particularly the complex relationships between lipid metabolism, inflammation, and endoplasmic reticulum stress (ERS), is crucial for improving treatment strategies. This study proposes the hypothesis that "melatonin (MT) alleviates ERS-mediated inflammation in adipose tissue" and explores its mechanism of action. The results showed that MT effectively reduce ERS and its induced inflammatory response in adipose tissue and adipocytes of mice. Mechanistically, MT regulates the expression of the key ERS gene activating transcription factor 6(ATF6) by reducing the methylation level of the circadian clock gene period1 (PER1). Additionally, the study found that PER1 specifically binds to the promoter region of ATF6, thereby negatively regulating its expression and alleviating ERS. We also reveal that MT can effectively mitigate inflammation pathways mediated by ERS, including macrophage polarization and NOD-like Receptor family pyrin domain containing 3 (NLRP3) inflammasome activation. This research not only uncovers the significant role of MT in regulating obesity-related inflammation but also provides new insights for future intervention strategies targeting obesity and its complications. A deeper understanding of the role and mechanism of MT in regulating ERS can lay the foundation for the development of new drugs for the treatment of obesity and metabolic diseases and provide enormous potential for clinical applications.

ATF6; ERS; Inflammation; MT; Macrophage; PER1.