Multitissue single-cell analysis reveals differential cellular and molecular sensitivity between fructose and high-fat high-sucrose diets.

Metabolic syndrome (MetS), a conglomerate of dysregulated metabolic traits that vary between individuals, is partially driven by modern diets high in fat, sucrose, or fructose and their interactions with host genes in metabolic tissues. To elucidate the roles of individual tissues and cell types in diet-induced MetS, we performed single-cell RNA sequencing on the hypothalamus, liver, adipose tissue, and small intestine of mice fed high-fat high-sucrose (HFHS) or fructose diets. We found that hypothalamic neurons were sensitive to fructose, while adipose progenitor cells and macrophages were responsive to HFHS. Ligand-receptor analysis revealed lipid metabolism and inflammation networks among peripheral tissues driven by HFHS, while both diets stimulated synaptic remodeling within the hypothalamus. mt-Rnr2, a top responder to both diets, mitigated diet-induced MetS by stimulating thermogenesis. Our study demonstrates that HFHS and fructose diets have differential cell type and network targets but also share regulators such as mt-Rnr2 to affect MetS risk.