ABSTRACT: Despite the importance of genetic factors to metabolic health, the cellular and molecular mechanisms mediating interindividual variation in progression along the continuum from health to type 2 diabetes mellitus (T2D) remain incompletely characterized. We studied three genetically diverse mouse strains with variable baseline metabolic physiology and distinct responses to a high fat high sugar diet. To understand genetically encoded differences in cell type-specific responses to diet, we profiled two key metabolic tissues, white adipose and pancreatic islets, using single cell gene expression and chromatin accessibility. In both tissues, strain background most strongly influenced both cell composition and cell type-specific gene expression, with substantial but smaller contributions of biological sex and diet. Transcriptomics and chromatin profiling revealed considerable differences between strains in immune infiltration in both tissues. Mechanisms of adipose expansion and energy utilization differed between strains, highlighting the importance of metabolite transport (Acly, Slc25a1), catecholamine signaling (Adrb3, Gpr143), preadipocyte cell fate (Cd81), and adipocyte subsets with thermogenic capabilities (Ckb, Ucp1, PGC-1ɑ). Gene expression patterns in pancreatic beta cells were unique in the most resilient mouse strain, pointing to the importance of beta cell maturation pathways (Mafa, Ucn3), glucose metabolism (Glp1r), the unfolded protein/endoplasmic reticulum stress response (Atf6, Wfs1), and oxidative stress (Atox1) in the face of increased demand for insulin and glucolipotoxicity. Transcription of the adipokine Adipsin (Cfd) demonstrated a cross-tissue link consistent with the preservation of beta cell health in CAST mice. Finally, linking obesity and T2D GWAS effector genes to chromatin and transcriptional signals in the mouse revealed plausible cell types and states where variants mediating human disease traits likely exert their effects. Overall, this single cell atlas of key metabolic tissues provides insights into inherited variability in metabolic susceptibility and resilience and serves as a framework for utilizing diverse mice to study the progression of complex disease in a controlled, reproducible system.
