Poor sleep and fatty foods may reprogram metabolism in young mice

Both sleep disruption and high-fat (HF) diet are known risk factors for metabolic disorders, yet their synergistic impact during early development remains poorly understood. We explored whether postweaning sleep fragmentation (SF) programs subsequent metabolic vulnerability in mice concurrently challenged with an HF diet. Male ICR mice were assigned to four groups: CON, SF (SF from Postnatal day [PND] 21-42), CON-HF, and SF-HF (HF diet from PND28-56). We monitored body weight and caloric intake, performed glucose tolerance tests, and profiled gut microbiota (16S rRNA) and colonic metabolome (LC-MS). SF-HF mice exhibited weight gain despite significantly reduced caloric intake. Microbiome analysis showed selective enrichment of short-chain fatty acid (SCFA)-producing genera (*Lachnospiraceae_UCG-001*, [Eubacterium] groups). Metabolomics showed alterations in metabolites suggestive of SCFA modulation (e.g., increased glycerol tripropanoate), suppressed endocannabinoid signaling (e.g., linoleoyl ethanolamine), and altered arachidonic acid/glycerophospholipid metabolism. Correlation analysis associated these changes with specific bacterial-metabolite networks. Early-life SF combined with a concurrent HF diet results in altered profiles consistent with a dysfunctional SCFA-endocannabinoid axis. This reprogrammed metabolic state demonstrates how early-life sleep and nutritional quality can influence lasting metabolic health.