Chrononutritional regulation of metabolic homeostasis: intermittent fasting through gut microbiota, circadian rhythms, and autophagy

Abstract

The global obesity epidemic has increased the burden of metabolic diseases. Dietary interventions are key to managing obesity and improving metabolic health. Intermittent fasting (IF) has emerged as a promising chrononutritional intervention that may modulate metabolic metabolic homeostasis through timed eating–fasting cycles. This review examines four main IF patterns:time-restricted feeding (TRF), alternate day fasting (ADF), the 5:2 fasting, and the 4:3 fasting, and evaluates their effects on body weight, glucose homeostasis, insulin sensitivity, and lipid profiles. Furthermore, it delineates the mechanistic pathways through which IF confers metabolic benefits beyond caloric restriction alone: (1) alleviating insulin resistance by enhancing the intestinal mucosal barrier and upregulating GLP-1 expression suppressing endotoxemia-related inflammation; (2) restoring circadian rhythmicity in the expression of metabolism-related genes to correct metabolic dysregulation; (3) increasing energy expenditure and lipid oxidation via short-chain fatty acid-mediated browning of white adipose tissue (WAT); and (4) enhancing cellular autophagy through activation of the SIRT3–AMPK–mTOR signaling pathway, thereby improving overall metabolic function. Evidence supports IF as a potentially effective alternative for obesity and metabolic disorders through chronobiological mechanisms. However, potential adverse effects like hypoglycemia and adherence challenges highlight the need for individualized approaches in clinical practice.