Abstract 16492: MiR-92a Controls Metabolism and Obesity
Obesity and type 2 diabetes are key risk factors for the development of coronary artery disease. MicroRNAs (miRs) are small non-coding RNA molecules, which act as negative regulators of gene expression and have been shown to modulate cardiovascular diseases and control energy homeostasis. MiR-92a belongs to the miR-17~92 cluster and pharmacological inhibition of miR-92a improved neovascularization and endothelial cell functions. To determine the metabolic function of miR-92a, we analyzed the phenotype of genetic and pharmacological miR-92a depletion on obesity.
We showed that miR-92a-/- mice are resistant against high-fat diet (HFD) induced obesity (weight gain from 6-14.5 weeks of age: -24±4% vs. WT; p<0.01). Weight of epididymal WAT (-54±9% vs. WT; p=0.04) as well as the percentage of total body fat measured by dual energy X-ray absorptiometry (-20±6% vs. WT; p=0.04) was reduced in miR-92a-/- mice. Consistently, white adipocyte cell size was reduced in miR-92a-/- mice (-24±7% vs. WT; p=0.03). Furthermore, plasma cholesterol (-27±6% vs. WT; p<0.01) and triglyceride (-25±4% vs. WT; p=0.02) levels of miR-92a-/- mice were lowered. A glucose tolerance test further showed that miR-92a-/- mice have an improved glucose tolerance (AUC: -21±6% vs. WT; p=0.04).
Next we tested whether pharmacological inhibition of miR-92a by LNA-based antimiRs (LNA-92a) can reduce obesity in db/db mice. Therefore we treated 4.5 months old db/db mice with LNA-92a (5 mg/kg i.p.) once a week over 16 weeks. LNA-92a treated mice showed a reduction of body weight compared to LNA-Control (LNA-Co) and untreated mice (-25±6% vs. LNA-Co and untreated mice; p<0.01). Likewise, the body mass index was reduced (-21±3% vs. LNA-Co and untreated mice; p<0.001). Furthermore, pericardial fat was profoundly lower in the LNA-92a group (-43±11% vs. LNA-Co and untreated mice; p=0.01). Consistently, administration of LNA-92a reduced systemic levels of cholesterol (-28±4% vs. LNA-Co and untreated mice; p<0.01) and triglycerides (-43±6% vs. LNA-Co and untreated mice; p=0.01).
In summary, both studies clearly demonstrate that miR-92a controls obesity. Inhibition of miR-92a might therefore be a promising strategy to improve endothelial cell functions and at the same time reduce metabolic syndromes.
- © 2013 by American Heart Association, Inc.