Single Nuclei Transcriptomics Reveals Obesity-Induced Endothelial and Neurovascular Dysfunction: Implications for...

Area of Science:

• Neuroscience
• Genomics
• Metabolic Disorders

Background:

• Obesity is linked to cardiovascular disease and vascular dementia.
• The impact of obesity on brain endothelial cell genomics and neurovascular unit (NVU) interactions is not well understood.

Purpose of the Study:

• To characterize obesity-induced transcriptomic changes in the NVU of the mouse hippocampus.
• To investigate the relationship between obesity, NVU cell types, and blood-brain barrier (BBB) permeability.

Main Methods:

• Single nuclei RNA sequencing (snRNAseq) was performed on hippocampal NVU cells (endothelial cells, astrocytes, microglia, neurons) from obese (ob/ob) and wild-type (WT) mice.
• Blood-brain barrier permeability was assessed using gadolinium-enhanced MRI.
• Differentially expressed genes (DEGs) and pathways were analyzed.

Main Results:

• Obese mice exhibited obesity, hyperinsulinemia, and impaired glucose tolerance.
• snRNAseq identified DEGs across all NVU cell types, with significant changes in neurons and astrocytes.
• Common pathways affected included focal adhesion and insulin signaling; angiogenesis and synaptic trafficking were also identified.
• A trend toward increased BBB permeability was observed in obese mice.
• Differentially expressed long non-coding RNAs (lncRNAs) were found in pathways like TNF and mTOR.

Conclusions:

• Obesity induces widespread transcriptomic alterations in the hippocampus's NVU.
• These changes provide molecular insights into obesity-related cognitive dysfunction.
• Findings suggest potential targets for gene therapy to address cognitive decline in obesity.