Time-restricted feeding induces white adipose browning and improves metabolic health independent of weight loss: an integrative multi-omics study

Aims: Time-restricted feeding (TRF) exerts beneficial effects against metabolic disorders via adipocyte thermogenesis; however, the precise tissue-specific mechanisms and key molecular mediators remain incompletely characterized. Materials and methods: C57BL/6J male mice were subjected to a 9-week high-fat, high-fructose diet (HFHFD) before being randomized into one of three groups for an additional 9 weeks: continued HFHFD group, high-fat diet (HFD) group, or TRF group fed with HFD. Body weight, adipose tissue mass, and serum lipids and glucose levels were measured. Proteomic analysis of inguinal white adipose tissue (iWAT) was conducted in the HFD and TRF groups, and plasma metabolome and lipidome profiles were analyzed across all three groups. Key findings: Compared to HFD, TRF significantly reduced serum low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and resistin levels, without accompanying weight loss. TRF reduced iWAT mass and upregulated mRNA expression of thermogenic genes (PGC-1a and UCP-1). Proteomic analysis revealed that TRF upregulated mitochondrial electron transport chain (ETC) complex I proteins and activated iWAT oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. TRF notably altered the plasma lipidome and metabolite profiles, with polyunsaturated phosphatidylcholines (PUFA-PCs) accounting for approximately half of the differential lipids and D-2-hydroxyglutaric acid (D2HG) being significantly decreased. Significance: In summary, multi-omics profiling reveals that TRF improves metabolic health in HFHFD-fed mice independent of weight loss by enhancing iWAT thermogenesis through mitochondrial OXPHOS, with specific upregulation of ETC complex I proteins. Additionally, TRF remodels plasma lipidome and metabolite signatures, including reduced D2HG and PUFA-PCs, which may serve as novel biomarkers of TRF efficacy.