Intermittent time-restricted feeding recapitulates the physiological benefits of daily time-restricted feeding in male mice with chronic metabolic disease

Time-restricted feeding (TRF) is proposed as a relevant strategy to counteract obesity and metabolic disorders; however, the therapeutic efficacy of more pragmatic intermittent TRF (iTRF) regimens remains undefined. Herein, daily and intermittent TRF significantly improved whole-body physiology, promoted key hallmarks of energy restriction, and induced coordinated transcriptional and lipidomic remodeling in male mice with chronic metabolic dysfunction previously established by prolonged high-fat, high-cholesterol, high-fructose feeding. These effects were summarized using three composite scores capturing physiological/metabolic, energy restriction, and lipidic responses, which consistently separated daily and intermittent TRF regimens from ad libitum -fed mice. Lipidomic profiling identified a subset of hepatic lipids associated with systemic health, pointing to lipid remodeling, particularly at the endoplasmic reticulum, as a potential feature of the TRF response. Notably, TRF failed to histologically improve hepatic steatosis, ballooning, or inflammation, and its overall benefits were clearly inferior to dietary normalization to standard chow diet. Altogether, these data (i) demonstrate that intermittent TRF recapitulates the beneficial effects in advanced metabolic disease, (ii) provides translational support for flexible TRF strategies, and (iii) highlights the need to integrate TRF with additional therapeutic strategies.