Prior high fiber intake impinges on the cellular responses of mesenteric adipose and intestinal tissues to subsequent high fat feeding.

While high-fiber diets (HfiDs) promote weight loss, their long-term efficacy is limited by rapid weight regain upon returning to high-fat diets (HFDs). Using C57BL/6J mice in diet-switching paradigms, we characterized tissue-specific responses to HfiD-to-HFD transitions through single-nucleus and spatial transcriptomics. HfiD pre-feeding enhanced mesenteric white adipose tissue progenitor/adipocyte sensitivity to subsequent HFD exposure. In the intestine, HfiD prevented HFD-induced immune-enterocyte expansion in the duodenum and reversed the enterocyte-to-goblet cell shift in the colon while maintaining persistent epigenetic reprogramming. Although HfiD-induced microbiome changes were largely reversed by HFD, we identified sexually dimorphic remodeling of adipose cell populations during diet transitions. Our findings demonstrate that prior HfiD feeding fundamentally reprograms adipose and intestinal responses to subsequent HFD challenge, providing mechanistic insights into dietary intervention outcomes. This work establishes a spatiotemporal resource for understanding tissue plasticity during dietary changes, offering new perspectives for obesity management strategies.