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*For medical professionals only
In the past ten years, with the improvement of living standards, diabetes has become more and more common
.
Up to now, there are more than 100 million diabetic patients in China, of which about 95% suffer from type 2 diabetes mellitus (T2D) [1].
The prevalence of diabetes in China has also developed from less than 1% in 1980 to 12.
4% in 2018 [1].
Studies have shown that patients with T2D who are obese or abdominally obese are at higher risk of cognitive impairment [2-4].
However, the role of adipose tissue in cognitive dysfunction in diabetes is poorly
understood.
Recently, a research team led by Professor Bi Yan of Gulou Hospital affiliated to Nanjing University School of Medicine published important research results in Cell Metabolism [5].
Studies have found that adipose tissue-derived extracellular vesicles (EVs) in diabetics induce cognitive dysfunction
.
The researchers also noted that EVs mediate cognitive dysfunction through their contents microRNA (miRNA) miR-9-3p
.
The study shows that adipose tissue plays an important role
in the development and development of cognitive dysfunction in diabetic patients.
Targeting adipose tissue-derived EVs or miRNAs may treat cognitive dysfunction
in diabetics.
Screenshot of the front page of the paper
Next, let's take a look at how Bi Yan's team carried out this
research.
In order to explore the role of adipose tissue in diabetic cognitive dysfunction, the researchers first established an animal model of
fat grafting.
The researchers transplanted VAT from high-fat diet (HFD) mice that lacked visceral adipose tissue (VAT) in their diet (Figure 1A).
The researchers found that fat transplant mice developed cognitive dysfunction and neuronal damage compared to normal mice, mainly manifested by longer escape latency in hidden platform tests (Figure 1B), less time in the target quadrant (Figure 1C), significantly reduced preference for new subjects (Figure 1D), and significantly reduced number of hippocampal synapses (Figure 1E).
Figure 1.
Adipose tissue impairs cognitive function in high-fat diet mice
Adipose tissue is considered to be the largest endocrine organ, which can produce a variety of biologically active factors such as EVs, which regulate different organ functions [6].
The researchers speculate that EVs produced by adipose tissue may play a role
.
As expected, synaptic damage in mouse neurons decreases after adipose tissue (AT) removes EVs (Figure 2).
Figure 2.
Adipose tissue EVs impair mouse neuronal function
These results suggest that EVs produced by adipose tissue may mediate diabetic cognitive dysfunction
.
To explore its function, the researchers injected adipose tissue-derived EVs (DM-AT-EVs) from diabetic patients into normal mice through the tail vein
.
It was found that DM-AT-EVs treatment aggravated cognitive dysfunction and significantly reduced the number of
synapses in mice compared to mice injected with AT-EVs (nonDM-AT-EVs) from non-diabetic patients.
It has been pointed out that miRNAs in AT-EVs play a key role in the functional regulation of recipient tissues [7].
The researchers speculate that AT-EVs may promote cognitive impairment
in mice through miRNAs.
To test this hypothesis, the researchers blocked the expression of the miRNA processing enzyme Dicer (AAV-siDicer) by small RNA interference technique (siRNA).
As expected, AAV-siDicer effectively inhibits Dicer expression and significantly reduces miRNA expression levels in HFD-AT-EVs (Figure 3B).
In addition, siDicer-EVs-treated mice performed better on cognitive-behavioral tests and weakened
synaptic loss compared to controls.
These results suggest that miRNAs in AT-EVs are key molecules
leading to cognitive dysfunction in mice.
Figure 3.
After interference with Dicer, AT-EVs miRNA is significantly reduced
So specifically, which miRNA exacerbates cognitive impairment?
After deep RNA sequencing of AT-EVs in normal mice and AT-EVs in HFD mice, it was found that only miR-9-3p showed an upward trend
in HFD mice and diabetics.
In addition, the investigators recruited two clinical cohorts to verify whether elevated miR-9-3p levels in AT-EVs were associated
with cognitive impairment in humans.
In the first cohort, the investigators found that serum EVs in obese DM patients were significantly upregulated
compared to controls.
In another cohort, researchers passed the Montreal Cognitive Assessment (MoCA) of volunteers
with or without diabetes.
It was found that serum EVs miR-9-3p levels were significantly higher in diabetic patients than in non-diabetic patients
.
Diabetics with mild cognitive impairment had further elevated miR-9-3p levels compared to cognitively normal diabetics (Figure 4L).
In addition, correlation analysis showed that serum EVs miR-9-3p levels were negatively correlated with MoCA values (p=0.
003) (Figure 4M).
Figure 4.
Serum EVs miR-9-3p levels were significantly elevated in obese patients with DM
Because miRNAs typically regulate gene expression after transcription, the researchers also identified the target gene
for miR-9-3p.
After screening, the researchers found and determined that brain-derived neurotrophic factor (BDNF) is the target of miR-9-3p, and immunostaining and enzyme-linked immunosorbent assay (ELISA) showed that HFD mice had significantly lower
hippocampal BDNF levels compared to normal mice.
BDNF is known to play an important role in synapse formation, maintenance, and plasticity [8].
Finally, the researchers also evaluated its function
using a miR-9-3p inhibitor (AAV-miR-9-3p-sponge).
As expected, HFD mice injected with AAV-miR-9-3p-sponge had reduced
cognitive impairment and synaptic damage compared to controls.
Pattern diagram
In summary, the study has identified a new pathway for fat-brain information exchange, namely adipose tissue EVs
.
EVs of adipose tissue and their contents, miRNAs, induce synaptic damage and cognitive dysfunction
.
Mechanically, EVs function
via miR-9-3p.
Therefore, EVs or miRNAs may be drug targets for the treatment of cognitive impairment
associated with T2D.
Of course, this study also raises questions about whether EVs or miRNAs have tissue or organ preferences, whether EVs or miRNAs have other functions, and the source of miRNAs, and we look forward to more research data
in the future.
References:
[1] Wang Y, Zhao L, Gao L, Pan A, Xue H.
Health policy and public health implications of obesity in China.
Lancet Diabetes Endocrinol.
2021; 9(7):446-461.
doi:10.
1016/S2213-8587(21)00118-2
[2] Hu C, Jia W.
Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication.
Diabetes.
2018; 67(1):3-11.
doi:10.
2337/dbi17-0013
[3] HOU Rui.
(2022).
Overview of metabolic surgery in China to alleviate obesity type 2 diabetes.
Chinese Journal of Clinicians (07), 789-793.
[4] Xu WL, Atti AR, Gatz M, Pedersen NL, Johansson B, Fratiglioni L.
Midlife overweight and obesity increase late-life dementia risk: a population-based twin study.
Neurology.
2011; 76(18):1568-1574.
doi:10.
1212/WNL.
0b013e3182190d09
[5] Wang J, Li L, Zhang Z, et al.
Extracellular vesicles mediate the communication of adipose tissue with brain and promote cognitive impairment associated with insulin resistance.
Cell Metab.
2022; 34(9):1264-1279.
e8.
doi:10.
1016/j.
cmet.
2022.
08.
004
[6] Scherer PE.
The many secret lives of adipocytes: implications for diabetes.
Diabetologia.
2019; 62(2):223-232.
doi:10.
1007/s00125-018-4777-x
[7] Thomou T, Mori MA, Dreyfuss JM, et al.
Adipose-derived circulating miRNAs regulate gene expression in other tissues [published correction appears in Nature.
2017 May 10; 545(7653):252].
Nature.
2017; 542(7642):450-455.
doi:10.
1038/nature21365
[8] Kowiański P, Lietzau G, Czuba E, Waśkow M, Steliga A, Moryś J.
BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity.
Cell Mol Neurobiol.
2018; 38(3):579-593.
doi:10.
1007/s10571-017-0510-4
Responsible EditorZhang Jinxu