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Intermittent fasting (IF) has gained attention as a potential intervention for cardiometabolic health, though its long-term effects remain unclear. In this randomized clinical trial, we assessed the impact of 6 months of IF on body composition, cardiovascular risk factors, and related molecular pathways in middle-aged (30-65 years) men and women with overweight (BMI 24.8–35 kg/m²). In this trial, 41 participants were randomized to either an intermittent fasting (IF) intervention or to maintain their habitual diet. The primary outcome (circulating CRP concentration) was previously reported; here, we present exploratory analyses focusing on metabolomic and transcriptomic responses. IF led to an 8% reduction in body weight, a 16% decrease in body fat, and significant improvements in lipid profile, including substantial reductions in plasma LDL-cholesterol, non-HDL-cholesterol, and triglycerides (p = 0.001). However, no significant changes were observed in other cardiometabolic risk factors. To investigate the underlying molecular mechanisms, we performed untargeted plasma metabolomics and transcriptomic analysis of colon mucosa biopsies. Significant multi-omic changes were identified, particularly in lipid metabolism, bile acid signaling, and enteroendocrine regulation. Notably, there was a downregulation of transcripts related to glucagon-like peptide 1 (GLP-1) and related enteroendocrine hormones. Correlation analysis highlighted key molecular pathways, with PPAR-α and B-cell-mediated immune processes significantly associated with changes in non-HDL cholesterol. Our findings extend the understanding of IF in humans beyond weight loss, providing key mechanistic insights to inform targeted therapies for improving cardiometabolic health. ClinicalTrials.gov NCT01964118 Intermittent fasting is investigated as an alternative to caloric restriction as a treatment modality for weight loss and improvement of cardiometabolic risk factors. Here the authors report the secondary and exploratory outcomes of a randomized controlled cross-over trial showing that six months of intermittent fasting reduced body weight and improved lipid profiles, which associated with altered GLP−1–related enteroendocrine signaling and B-cell pathways based on colon transcriptomics and plasma metabolimics.
Barve et al. (Sat,) studied this question.