Letter: Clarifying the Synergistic Mechanisms of Mediterranean Diet and Time-Restricted Feeding in MASLD Management

Abstract

The CHRONO-NAFLD trial by Tsitsou et al. [1] provides valuable insights into combining Mediterranean diet (MD) and time-restricted feeding (TRF) for metabolic dysfunction-associated steatotic liver disease (MASLD). While the study demonstrates comparable weight loss across groups and superior glycemic benefits with early TRF, three critical questions warrant further discussion to contextualise these findings.

First, the caloric restriction confounder limits mechanistic interpretation. All groups followed a hypocaloric MD (−500 kcal/day), which itself drives weight loss and metabolic improvements. Prior studies show that TRF's benefits on hepatic steatosis and insulin sensitivity are most pronounced in ad libitum feeding models [2]. By superimposing TRF on caloric restriction, the independent effects of circadian alignment may be obscured. Future trials should isolate TRF's impact by comparing isocaloric TRF vs. non-TRF arms.

Second, the lack of circadian biomarker data (e.g., melatonin, cortisol rhythms) leaves a key knowledge gap. TRF's efficacy likely depends on synchronising food intake with endogenous circadian clocks regulating hepatic metabolism [3]. The differential glycemic outcomes between eTRF and lTRF groups suggest timing-specific effects on insulin signalling pathways, potentially mediated by clock gene modulation (e.g., BMAL1, PER2). Including circadian phase assessments would clarify whether clinical benefits correlate with restored rhythmicity.

Lastly, heterogeneity in baseline metabolic dysfunction (e.g., 34% with diabetes, 61% with metabolic syndrome) may have diluted intervention effects. Subgroup analyses stratified by glycemic status or fibrosis severity could identify patients most likely to benefit from TRF-MD synergy. For instance, prediabetic patients showed greater HbA1c reductions in eTRF (−0.3%), aligning with evidence that circadian interventions preferentially improve early dysmetabolism [4].

While this trial confirms MD's foundational role in MASLD, unravelling the chronobiological mechanisms of TRF and personalising its application remain critical next steps.

Weixiong Zhu: conceptualization, writing – original draft, investigation. Wence Zhou: writing – review and editing, funding acquisition.

This article is linked to Tsitsou et al papers. To view these articles, visit https://doi.org/10.1111/apt.70044 and https://doi.org/10.1111/apt.70178.