Short-term time-restricted feeding improves metabolic rhythms and liver mitochondrial bioenergetic function in high fat diet-fed mice

Time-restricted feeding (TRF), which confines food intake to specific time periods without altering nutrient content or reducing calories, has shown promise in improving cardiometabolic health. This study tested whether a two-week TRF intervention during the active (dark) period could reverse long-term effects of a high fat diet (HFD) on liver mitochondrial function, steatosis, and metabolism in mice. Male C57BL/6J mice were fed either a normal fat diet (NFD, 10% kcal fat) or a HFD (45% kcal fat) ad libitum for 18 weeks, followed by two weeks of active period TRF. Assessments included whole-body metabolism, gene expression, histopathology, plasma lipid levels, and mitochondrial bioenergetic function. Chronic HFD feeding abolished the day-night difference in the respiratory exchange ratio (RER), altered 24-h expression rhythms of clock, lipid, and mitochondrial metabolism genes in the liver, and eliminated diurnal variation in liver mitochondrial bioenergetics. TRF partially restored RER rhythmicity without altering body composition or reducing caloric intake in HFD mice. TRF also restored 24-h expression rhythms in clock and several metabolic genes, normalized liver and plasma triglyceride oscillations, and reduced small droplet macrosteatosis in livers of HFD mice. Importantly, TRF improved liver mitochondrial respiration and reduced circulating levels of mitochondrial transcription factor A (mtTFA), a mitochondrially-derived damage-associated molecule pattern (mtDAMP), indicating reduced mitochondrial injury in HFD mice. These findings suggest that TRF can rapidly reverse HFD-induced disruptions in metabolic and mitochondrial function, offering a promising new non-pharmacologic strategy for improving liver health in obesity-related metabolic disease.