Recent research indicates that exposure to fine particulate matter (PM2.5) not only impairs the respiratory system but also disturbs adipose tissue homeostasis, contributing to rising obesity rates and systemic metabolic disturbances. Time-restricted feeding (TRF), a dietary approach that confines daily food consumption to specific time windows, has demonstrated significant potential in preventing and managing metabolic disorders. However, it remains unclear if TRF can alleviate PM2.5-induced adipose tissue dysfunction, and the mechanisms involved require investigation. We established a PM2.5-exposed male mouse model and randomly assigned the animals to four groups: filtered air (FA), PM2.5 exposure, TRF+FA, and TRF+PM2.5. The PM2.5 and TRF+PM2.5 groups underwent whole-body PM2.5 exposure in inhalation chambers, while the remaining groups were maintained under FA conditions. Mice in the TRF+FA and TRF+PM2.5 groups were subjected to an 8-h feeding window during the active phase (ZT16-ZT24). Our results indicated that PM2.5 exposure induced systemic energy metabolism dysregulation and obesity, characterized by reduced heat production and metabolic rate, along with adipocyte hypertrophy, lipid droplet expansion, adipokine dysregulation, and inflammatory activation in both inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT). Furthermore, PM2.5 significantly suppressed thermogenesis, impaired oxidative phosphorylation, disrupted mitochondrial quality control networks, and downregulated the AMPK/SIRT1/PGC-1α signaling pathway. Notably, TRF intervention reactivated these signaling pathways, systematically reversed the multi-level pathological alterations, and restored mitochondrial homeostasis and energy metabolic balance. This study suggests for the first time that TRF counteracts adipose tissue dysfunction caused by PM2.5, offering a promising lifestyle intervention strategy against environment-related metabolic diseases.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most common metabolic syndromes worldwide. Its pathogenesis is multifactorial, involving disruptions in lipid metabolism, insulin resistance, chronic inflammation, and mitochondrial dysfunction. Veratric acid (VA), a naturally occurring phenolic compound, is known for its antioxidant and anti-inflammatory properties; however, its therapeutic potential and underlying mechanisms in the context of MAFLD remain largely uncharacterized. This study aimed to investigate the protective effects and underlying mechanisms of VA in a high-fat diet induced mouse model of MAFLD. In this study, C57BL/6J mice were fed an HFD with or without VA supplementation. Metabolic phenotypes, hepatic steatosis, and serum biochemical parameters were evaluated. In vitro experiments were conducted in HepG2 cells to assess lipid accumulation, mitochondrial function, oxidative stress, and gene expression. Network pharmacology, molecular docking, CETSA, and DARTS assays were employed to identify potential targets. The results demonstrated that VA significantly alleviated HFD-induced weight gain, adipose tissue accumulation, and hepatic steatosis. VA also improved glucose homeostasis, reduced serum lipid levels, and ameliorated liver injury. Mechanistically, VA modulated lipid metabolism by enhancing fatty acid β-oxidation and lipolysis. Network pharmacology, molecular docking, and biochemical validation further identified peroxisome proliferator-activated receptor gamma (PPARG) as a key target of VA. VA stabilized the PPARG protein, thereby promoting lipid metabolic reprogramming. These findings provide new insights into the bioactivity of VA and suggest its potential as a natural therapeutic agent for MAFLD.
