Adipose tissue coregulates cognitive function

Abstract

Obesity is associated with cognitive decline. Recent observations in mice propose an adipose tissue (AT)–brain axis. We identified 188 genes from RNA sequencing of AT in three cohorts that were associated with performance in different cognitive domains. These genes were mostly involved in synaptic function, phosphatidylinositol metabolism, the complement cascade, anti-inflammatory signaling, and vitamin metabolism. These findings were translated into the plasma metabolome. The circulating blood expression levels of most of these genes were also associated with several cognitive domains in a cohort of 816 participants. Targeted misexpression of candidate gene ortholog in the Drosophila fat body significantly altered flies memory and learning. Among them, down-regulation of the neurotransmitter release cycle–associated gene SLC18A2 improved cognitive abilities in Drosophila and in mice. Up-regulation of RIMS1 in Drosophila fat body enhanced cognitive abilities. Current results show previously unidentified connections between AT transcriptome and brain function in humans, providing unprecedented diagnostic/therapeutic targets in AT.

Mechanism of Microwave Radiation-Induced Learning and Memory Impairment Based on Hippocampal Metabolomics

“…The content of adipose tissue in brain is second only to adipose tissue, making brain function highly sensitive to disturbances in lipid metabolism [45]. Research has shown that gene expression in adipose tissue is associated with cognitive domains, contributing to the formation of neurons and synapses [46]. Moreover, disturbances in lipid metabolism may also impact inflammatory responses and oxidative stress, thereby exacerbating cognitive decline.…”

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

“…This risk represents a modifiable factor in neurodegenerative processes [1,4], suggesting that dietary components could serve as preventive measures. Several explanations for the link existing between obesity and AD have been proposed [34,35]. One possibility is that obesity enhances inflammation in the brain, which can damage neurons and promote the development of AD [36].…”

Impaired Remodeling of White Adipose Tissue in Obesity and Aging: From Defective Adipogenesis to Adipose Organ Dysfunction

“…Briefly, conditional knockdown of SLC18A2 in AT reversed memory impairment induced by HFD in mice. Furthermore, downregulation of Vmat (the Drosophila orthologue of SLC18A2) improved short-term memory, while overexpression of Rim (RIMS1 orthologue) enhanced learning abilities in Drosophila [289]. In the search for accessible biomarkers with prognostic and predictive value, gene expression in peripheral blood mononuclear cells was assessed, revealing that genes associated with cognition in AT (NUDT2, AMPH, UNC5B, OAT, EZR, and NR4A2) exhibited similar associations with cognitive traits across 816 subjects [289].…”

“…Furthermore, downregulation of Vmat (the Drosophila orthologue of SLC18A2) improved short-term memory, while overexpression of Rim (RIMS1 orthologue) enhanced learning abilities in Drosophila [289]. In the search for accessible biomarkers with prognostic and predictive value, gene expression in peripheral blood mononuclear cells was assessed, revealing that genes associated with cognition in AT (NUDT2, AMPH, UNC5B, OAT, EZR, and NR4A2) exhibited similar associations with cognitive traits across 816 subjects [289]. These findings reinforce the concept of targeting AT as a therapeutic strategy for cognitive dysfunction, by identifying potential biomarkers and clinically relevant therapeutic targets.…”

“…Unfortunately, this study [289] solely concentrated on individuals with severe obesity (BMI > 35 kg/m 2 ), thereby limiting its generalizability. To bolster these findings and broaden their applicability regarding the association between fat and cognitive dysfunction during aging, further research utilizing larger, longitudinal studies is imperative, especially with regards to older adults.…”