Molecular Mechanisms and Clinical Translation of Intermittent Fasting on Adipose Tissue Heterogeneity

Adipose tissue heterogeneity, particularly the pathogenic role of visceral adipose tissue (VAT) in metabolic diseases, poses significant clinical challenges. Current research confirms that intermittent fasting (IF) induces depot-specific adaptations: VAT exhibits lipid conservation mechanisms while subcutaneous adipose tissue (SAT) demonstrates thermogenic plasticity through microbiota crosstalk. The gut-liver axis further mediates systemic metabolic synchronization during IF. However, precise frameworks for stratifying IF protocols based on adipose biology remain underdeveloped. This review synthesizes molecular mechanisms driving VAT/SAT differential responses to IF, evaluates depot-specific efficacy of major regimens, and establishes a visceral fat ratio (VFR)-based precision framework. Key findings indicate that early time-restricted eating (eTRE) preferentially reduces VAT with glycemic stability, whereas alternate-day fasting (ADF) carries long-term rebound risks. Integration of circadian-aligned exercise and behavioral support significantly enhances intervention sustainability. This analysis provides clinically actionable stratification: high-VFR individuals benefit maximally from eTRE-exercise synergy, while moderate-VFR phenotypes require vigilant cardiometabolic monitoring during ADF. The framework addresses critical implementation barriers including lean mass preservation and adolescent contraindications. Future research should prioritize digital adherence platforms and biomarker-defined feeding windows to optimize personalization. This work establishes a mechanism-informed foundation for translating adipose-specific IF benefits while highlighting unresolved questions regarding long-term vascular impacts and tissue-specific circadian reprogramming.