The researchers identified that the expression of miR-181b was lower in adipose tissue endothelial cells, but not adipocytes, after just one week of high-fat feeding in mice. The team hypothesized that reconstituting this microRNA in obese mice might improve the development of insulin resistance/diabetes. Indeed, they found that injections of a miR-181b mimic into obese mice markedly improved insulin sensitivity, glucose levels and reduced inflammation in adipose tissue.
The team found that the protein phosphatase PHLPP2 is a direct target of miR-181b, and that suppression of the protein also improved insulin sensitivity, glucose levels and inflammation in mice, providing an additional new target for therapy.
Finally, the team noted that levels of PHLPP2 were higher in endothelial cells from diabetic patients than healthy patients, suggesting the new findings in mice are relevant to human disease.
"We have discovered a microRNA that functions to dampen the inflammatory response in the vasculature of adipose tissue by targeting endothelial cells that surround adipocytes and a pathway that leads to increased nitric oxide production," said senior author Mark W. Feinberg, an associate physician at BWH. "The beneficial role of this microRNA in obesity is likely the tip of the iceberg since excessive inflammation is a pervasive finding in a wide-range of chronic inflammatory diseases."
An accompanying editorial in the journal notes that "using microRNAs to modulate adipocyte-endothelial cell axis in adipose tissue may offer new tools to combat the growing epidemic of obesity and its associate comorbidities."
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Funding for this work came from the National Institutes of Health grants, the American Heart Association, the Arthur K. Watson Charitable Trust, and the Dr. Ralph and Marian Falk Medical Research Trust, a Jonathan Levy Research Fund, and a State Scholarship Fund of the China Scholarship Council.