Multitissue single-cell analysis reveals differential cellular and molecular sensitivity between fructose and...

Area of Science:

• Metabolomics
• Genomics
• Cell Biology

Background:

• Metabolic syndrome (MetS) is a complex condition influenced by diet and genetics.
• Modern diets high in fats, sucrose, or fructose are implicated in MetS development.
• Understanding tissue-specific responses to diet is crucial for addressing MetS.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms underlying diet-induced MetS.
• To identify distinct tissue and cell type responses to high-fat high-sucrose (HFHS) and fructose diets.
• To uncover shared and differential regulatory pathways affected by these diets.

Main Methods:

• Single-cell RNA sequencing was performed on mouse hypothalamus, liver, adipose tissue, and small intestine.
• Mice were fed either a high-fat high-sucrose (HFHS) diet or a fructose-rich diet.
• Ligand-receptor interaction analysis was employed to map cellular communication networks.

Main Results:

• Hypothalamic neurons responded uniquely to fructose, while adipose progenitor cells and macrophages were sensitive to HFHS.
• HFHS diet induced lipid metabolism and inflammation networks in peripheral tissues.
• Both diets promoted synaptic remodeling in the hypothalamus.
• mt-Rnr2 was identified as a key regulator mitigating MetS by enhancing thermogenesis.

Conclusions:

• HFHS and fructose diets exhibit distinct cellular and network targets in diet-induced MetS.
• Shared regulators, such as mt-Rnr2, play a role in modulating MetS risk across different dietary conditions.
• This research provides insights into the personalized cellular responses to metabolic challenges.