A Multi-tissue Transcriptomic-Metabolomic Map Linking Maternal High-Fiber Diet to Reduced Offspring Type 2 Diabetes

Abstract

BackgroundEarly-life nutritional exposures are increasingly recognized as critical determinants of long-term metabolic health, yet the molecular mechanisms linking maternal diet to offspring type 2 diabetes susceptibility remain incompletely understood. Experimental models are essential to disentangle maternal dietary effects from later-life metabolic influences. MethodsUsing the Nile rat, a genetically heterogeneous model of diet-induced diabetes, we quantified the impact of maternal high-fiber diet on offspring diabetes incidence using sex-stratified time-to-event analyses in 762 offspring. To identify molecular mediators, we performed transcriptomic profiling across 13 offspring tissues, independently contrasting maternal diet exposure and early-onset diabetes status. Overlapping differentially expressed genes were prioritized and evaluated for cardiometabolic associations in human whole-blood transcriptomic data from the GENE-FORECAST cohort. Untargeted plasma metabolomics was integrated to identify circulating metabolites associated with candidate genes. ResultsOffspring born to dams maintained on a high-fiber diet exhibited a markedly reduced risk of developing type 2 diabetes, with approximately 70% lower hazard of diabetes onset in both males and females compared with offspring from regular chow-fed dams. Multi-tissue transcriptomic analyses identified 147 genes differentially expressed in association with both maternal diet and early-onset diabetes, with most effects being tissue-specific. Asnsd1 uniquely showed consistent regulation across the aorta, brown adipose tissue, and skeletal muscle, with higher expression in offspring exposed to a high-fiber maternal diet and lower expression in offspring with early-onset diabetes. In human whole-blood transcriptomic data, ASNSD1 expression was significantly associated with blood pressure-related cardiometabolic traits, including hypertension, systolic blood pressure, and mean arterial pressure. In the animal model, circulating succinic acid was positively correlated with Asnsd1 expression in the aorta but not in other tissues. ConclusionsThis study provides a multi-tissue transcriptomic-metabolomic framework linking maternal high-fiber diet to reduced offspring type 2 diabetes risk. The findings identify ASNSD1 as a maternal diet-sensitive gene associated with diabetes susceptibility across multiple tissues and with cardiometabolic traits in humans, while highlighting tissue-specific relationships between gene expression and circulating metabolites. Together, these results offer mechanistic insight into how early-life nutrition can durably influence diabetes risk across the life course.