Exosomes carrying microRNAs regulate insulin sensitivity


Findings of a new study appearing in the journal Cell add to the growing body of evidence that exosomes carrying microRNAs (miRNAs) play a key role in insulin resistance in diabetes.

The study, led by researchers from UC San Diego School of Medicine and Chinese Academy of Medical Sciences & Peking Union Medical College, shows that exosomes from obese mice trigger insulin resistance in lean mice while exosomes from lean mice restore insulin sensitivity in obese mice.

Obesity and type 2 diabetes are closely linked. It is a well-known fact that overweight and obese individuals are at greater risk of developing type 2 diabetes. Although the mechanism underlying this has not been fully understood, studies have suggested that chronic inflammation resulting from obesity is an important pathogenic mediator of the development of insulin resistance, which is a hallmark of type 2 diabetes.

Obesity is characterized by the expansion of adipose tissue and an inflammatory component. Adipose tissue contains various immune cells, including macrophages that promote tissue inflammation. Obesity can increase the numbers and activation levels of these immune cells in adipose tissue. For example, the percentage of macrophages within adipose tissue ranges from 10% in lean humans up to 40% in obese humans.

Many different cell types in the body release a small vesicle, known as exosome, which can circulate in the body. Exosomes carry many functional contents, including miRNAs. miRNAs modulate gene expression by binding to the target mRNA, resulting in decreased expression of the protein encoded by the mRNA.

In this work, the researchers looked at exosomes released by adipose tissue macrophages. They collected macrophages from adipose tissue of obese mice, and harvested their exosomes. Next, they administrated these 'obese' exosomes to lean mice, and noticed that it caused glucose intolerance and insulin resistance. In contrast, when the researchers treated obese mice with exosomes derived from adipose tissue macrophages of lean mice, they found that it improved glucose tolerance and insulin sensitivity.

Furthermore, the study showed that miR-155 was overexpressed in exosomes derived from adipose tissue macrophages of obese mice. Prior studies have shown that miR-155 inhibits PPARγ. Moreover, the PPARγ protein is the molecular target of a number of marketed drugs, including a class of drugs used in diabetes.

Besides miR-155, there may be other miRNAs in adipose tissue macrophage-derived exosomes which correlate with insulin resistance. Sequencing all of the mRNAs in exosomes may help determine genetic signatures of obesity and type 2 diabetes.

Jerrold Olefsky, corresponding author of the study and professor of medicine at UC San Diego, hopes that these mRNAs would lead to new targets of insulin-sensitizing drugs.
 
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