Cell Metab: Bi Yan's team at Nanjing University discovered for the first time that exosomes mediate fat-brain communication and promote the occurrence of cognitive dysfunction in diabetes

Diabetes significantly increases the risk of cognitive impairment, including mild cognitive impairment and dementia, and seriously threatens healthy survival
in old age.
However, clinical studies have shown that blood sugar control does not protect cognitive function
.
Therefore, there is an urgent need to further reveal the mechanism of diabetic cognitive dysfunction and find new strategies
that can treat diabetic cognitive impairment.

Adipose tissue dysfunction plays an important role
in the development of cognitive impairment.
Cytokines produced by adipose tissue such as leptin and adiponectin are related to the maintenance of cognitive memory function of the brain; At the same time, the inflammatory factors produced by fat can induce chronic central inflammatory response, impair hippocampal nerve function, and promote cognitive impairment
.
However, current interventions targeting these adipose tissue-related mechanisms have not been able to reverse the progression of
cognitive impairment.

In addition to soluble adiposites, recent studies have found that adipose tissue can also secrete extracellular vesicles (EVs) as novel adipokines that play an important role in inter-organ communication, such as liver and skeletal muscle, and are involved in the development of
nonalcoholic fatty liver disease and type 2 diabetes.
However, whether EVs can mediate adipose tissue-brain communication is unknown
.

On September 6, 2022, Professor Bi Yan's team from the Department of Endocrinology, Gulou Hospital Affiliated to Nanjing University School of Medicine, and the team of Professor Zhang Chenyu and Associate Professor Li Liang from the School of Life Sciences, Nanjing University, published a paper in the journal Cell Metabolism entitled "Extracellular vesicles mediate the communication of adipose tissue with brain and promote" A research paper on cognitive impairment associated with insulin resistance found for the first time that exosomes mediate fat-brain communication and promote the occurrence
of cognitive dysfunction in diabetes.

The research team first used fat grafting to study the role of
adipose tissue in cognitive impairment in diabetes.
The results showed that normal mice experienced cognitive impairment and reduced
hippocampal synaptic density after transplanting adipose tissue from diabetic mice.
Further cell experiments showed that adipokines secreted by diabetic adipose tissue can cause neuronal synaptic damage, and removal of exosomes can significantly reduce this effect
.

In order to further investigate whether adipose tissue-derived EVs are directly involved in the occurrence of diabetic cognitive dysfunction, the researchers treated normal mice with high-fat mice and diabetic adipose tissue-derived EVs by tail vein injection and hippocampal stereotactic injection, respectively, and found that normal mice experienced significant synaptic loss and cognitive impairment
.
Further through EVs tracing technology, it was found that adipose tissue-derived EVs can be transported to the brain and enriched in hippocampal neurons
.
These results suggest that adipose tissue-derived EVs in diabetes have harmful effects
on cognitive function.

Previous studies have shown that miRNAs are key molecules
for biological function in adipose tissue EVs.
Subsequently, through virus-mediated gene editing technology, the researchers found that adipose tissue EVs can transport miRNAs to the hippocampal brain region, while targeted removal of miRNAs in adipose tissue EVs can reduce cognitive impairment
in diabetic mice.
Further, miRNAs in adipose tissue EVs that may cause cognitive impairment were analyzed by RNAseq, and it was found that miR-9-3p was significantly upregulated
in hippocampal and adipose tissue EVs in high-fat mice and adipose tissue EVs in diabetic patients.
Further validation found that miR-9-3p levels in adipose tissue, adipose tissue EVs, and serum EVs in obese diabetic subjects were significantly upregulated compared with normal subjects.
Serum miR-9-3p levels in patients with diabetes mellitus and mild cognitive impairment were significantly upregulated and negatively correlated with
MoCA cognitive scores.

Finally, they investigated the relationship between
miR-9-3p and cognitive impairment.
Inhibition of miR-9-3p in hippocampal or adipose tissue significantly alleviated diabetes-related synaptic damage and cognitive impairment
.
Further, through transcriptome sequencing and other methods, it was found that miR-9-3p induces synaptic damage
by targeting BDNF.

In summary, the innovation of the research is reflected in:

1) Discover a new fat-brain information exchange: adipose tissue EVs;

2) Discover a novel mechanism of diabetic cognitive dysfunction: diabetic adipose tissue EVs can cause synaptic loss and cognitive impairment;

3) Adipose tissue EVs and the miRNAs in them were found to be new targets for the treatment of potential diabetes cognitive dysfunction
.

Dr.
Zhang Zhou, Dr.
Zhu Ye, Master Zhang Xuhong, and Professor Zhang Chenyu, School of Life Sciences, Nanjing University, are the co-authors of the paper, Dr.
Zhang Zhou, Dr.
Zhu Ye, Master Zhang Xuhong and Professor Zhang Chenyu from the School of Life Sciences, Nanjing University, as co-authors, and Professor Bi Yan is the corresponding author
of the paper.

Original source:

Jin Wang， et al.
Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance.
Cell Metabolism， 2022.