Time-Restricted Feeding Is Not Effective in Modulating Fibrosis in a Male MASH Model

Time-restricted feeding (TRF), a dietary intervention that consolidates food intake to specific hours of the day, ameliorates key metabolic risk factors for metabolic-associated steatohepatitis (MASH), including adiposity, insulin resistance, and liver steatosis. However, whether TRF can directly mitigate steatohepatitis or fibrosis remains uncertain. Moreover, whether the protective effects of TRF against MASH-related complications, such as inflammation and fibrosis, depend exclusively on improvements in insulin sensitivity or involve additional mechanisms remains unknown. Here, we examine the impact of 8-hour TRF on the development of fibrosis and steatohepatitis using a streptozotocin/high-fat diet (STAM/HFD) model, which recapitulates key MASH characteristics, including steatohepatitis and fibrosis, in an insulin-deficient context. TRF does not prevent the development of MASH in STAM/HFD male mice where insulin signaling is impaired. Unlike diet-induced obesity models, which exhibit greatly perturbed feeding and circadian behaviors under HFD conditions, STAM/HFD mice did not develop obesity and maintained regular or less-pronounced disruptions to circadian behaviors. This may explain why TRF failed to produce beneficial effects in this model. These findings indicate that intact insulin signaling is likely essential for TRF to effectively protect against MASH.