Abstract 16501: Genetic Deletion and Pharmacological Inhibition of MiR-92a Reduce Obesity
Obesity and type 2 diabetes are key risk factors for coronary artery diseases. MicroRNAs (miRs) are small non-coding RNAs, which act as negative regulators of gene expression and have been shown to modulate cardiovascular diseases and control energy homeostasis. Inhibition of miR-92a improved neovascularization and endothelial cell (EC) function. To determine the metabolic role of miR-92a, we analyzed genetic and pharmacological miR-92a depletion on obesity.
MiR-92a-/- mice are resistant to high-fat diet (HFD) induced obesity (weight gain from 6-14.5 weeks of age: -24±4% vs. WT; p<0.01). The percentage of total body fat (dual energy X-ray absorptiometry: -20±6%; p=0.04), weight of epididymal white adipose tissue (WAT) (-54±9%; p=0.04), and consistently, white adipocytes size (-24±7%; p=0.03) were reduced in miR-92a-/- mice. Additionally, miR-92a-/- mice exhibit decreased levels of cholesterol (-27±6%; p<0.01) and triglyceride (-25±4%; p=0.02) as well as improved glucose tolerance (-21±6%; p=0.04).
Next, the ability of pharmacological miR-92a-inhibition via LNA-based antimiRs (LNA-92a) was tested in order to reduce obesity in db/db mice. Therefore, 4.5 months old db/db mice were either treated with LNA-92a or LNA-Control over a period of 16 weeks. LNA-92a treated mice showed a reduction of body weight compared to controls (-25±6%; p<0.01; body mass index: -21±3%; p<0.001). Furthermore, pericardial fat was decreased in the LNA-92a group (-43±11%; p=0.01). Consistently, administration of LNA-92a reduced systemic levels of cholesterol (-28±4%; p<0.01) and triglycerides (-43±6%; p=0.01).
To determine the mechanism by which miR-92a regulates obesity, we selectively depleted miR-92a in adipocytes (miR-92afl/flAdipo-Cre) and observed that these mice also showed a partially reduced weight gain after HFD induced obesity (-18±9%). Consistently, markers for brown adipose fat tissue (BAT) were increased in WAT suggesting that miR-92a-inhibition increases the formation of the more metabolically active BAT.
In summary, genetic and pharmacological inhibition of miR-92a reduces obesity and improves glucose tolerance and cholesterol levels. Therefore, blockage of miR-92a might be a promising strategy to reduce metabolic syndromes.
Author Disclosures: A. Fischer: None. D. Penzkofer: None. T. Seeger: None. A. Bonauer: None. A.M. Zeiher: None. S. Dimmeler: None.
- © 2014 by American Heart Association, Inc.