• Intermittent fasting ameliorated obesity-related metabolic dysregulation in high-weight cynomolgus monkeys. • Intermittent fasting-induced insulin reduction and improved insulin sensitivity were refractory to dietary reversal • Prolonged intermittent fasting disturbed the immunological homeostasis by elevating the lymphocyte-to-neutrophil ratio. • Intermittent fasting and refeeding induced slight gut microbial alternations and drove dynamic remodeling of serum metabolome. Dietary intervention has emerged as a promising approach for improving metabolic health across species; however, its systemic effects in non-human primates (NHPs) remain insufficiently characterized. We sought to investigate the metabolic and physiological impacts of time-restricted intermittent fasting (IF) regimen that resulted in a net energy deficit in overweight female cynomolgus monkeys, both during the intervention and after dietary reversal, with particular focus on body weight, metabolic parameters, immune cell ratios, gut microbiota, and serum metabolomic profiles. Overweight monkeys underwent 20-hour fasting/4-hour feeding IF protocol for 84 days, subsequently entering 42-day post-intervention phase where animals either continued IF (HW-IF-IF, n = 8) or resumed normal feeding (HW-IF-NF, n = 8). Normal-weight (Con-NF, n = 8) and high-weight control (HW-NF, n = 7) groups maintained standard feeding served as controls. We monitored body weight and measured serum triglycerides, insulin levels, and insulin resistance. Immune cell percentages were determined by flow cytometry. Gut microbiome was profiled via 16S rRNA sequencing. Serum metabolomic profiling was conducted using untargeted metabolomics. IF promoted significant reductions in body weight (day126, p = 0. 0421), serum triglycerides (day126, p = 0. 0108), insulin levels (day126, p = 0. 0107), and insulin resistance (day126, p = 0. 0004) in overweight monkeys. The insulin-lowering effects and enhanced insulin sensitivity were maintained even after reintroduction of normal feeding. By day 126, the sustained increase in lymphocyte-to-neutrophil ratio was exclusive to the continuous intermittent fasting group (HW-IF-IF), suggesting a potential immunomodulatory effect of prolonged fasting. Longitudinal gut microbiota analysis indicated that the gut microbiota structure underwent limited compositional changes. Nevertheless, time-dependent enrichments emerged in several genera, including Ruminococcus, Eubacteriumₕalliigroup, and Monoglobus. Serum metabolomics unveiled pronounced time-dependent alterations in circulating metabolites. These findings elucidate physiological and metabolic adaptations to specified IF-refeeding regimen in cynomolgus monkeys and establish a framework for mechanistic studies of fasting-induced metabolic responses in non-human primates.
Xu et al. (Sun,) studied this question.