Multitissue Single-Cell Analysis Reveals Differential Tissue, Cellular, and Molecular Sensitivity between Fructose and High fat high sucrose Diets

Metabolic syndrome (MetS) is a complex disorder with multidimensional etiology that encompasses diverse symptoms such as hyperlipidemia, abdominal obesity, and insulin resistance. Western diets such as the high fat high sucrose diet (HFHS) and those high in fructose ave been associated with increased prevalence of MetS. Despite the fact that various metabolic tissues have been implicated in MetS pathogenesis, the role of individual cell types embedded in these tissues has yet to be elucidated. To address this, we performed single cell RNA sequencing to examine thousands of individual cells from the hypothalamus, liver, adipose, and small intestine from both HFHS- and fructose-induced MetS mouse models. We found differential sensitivity of responsive cell types, genes, and pathways between HFHS and fructose diets, with hypothalamic neurons particularly sensitive to the high fructose diet and adipose progenitor cells particularly sensitive to HFHS diet. Network analysis identified both known (Avp, Apoe, C3) and novel ligands (Gal and Fga) that mediate ligand-receptor crosstalk between tissues in MetS. The identification of major cell types, molecular pathways, and regulators of MetS induced by different risk diets facilitates precision treatment of MetS subtypes. Chow (control), Fructose and HFHSeight-week-old C57BL/6J (B6) male mice were fed a chow diet with water, chow diet with water containing 15% fructose mimicking the prevalent uptake route of fructose through liquid drinks, and a high fat high sucrose diet containing 16.8% kcal protein, 51.4% kcal carbohydrate, and 31.8% kcal fat with water mimicking the Western diet for 11 weeks. Chow and water were changed once a week, and HFHS diet and fructose solutions were changed twice a week. Food and liquid were accessed ad libitum and the intake amount for each was measured. After 11 weeks, mice were sacrificed, and tissues including hypothalamus, gonadal adipose tissue, whole liver, and the small intestine (including duodenum, jejunum, and ileum) were collected for scRNA-seq using Drop-seq. For each tissue, n=2-5 independent biological replicates were processed from each diet group.