Long-term inhibition of miR-21 leads to reduction of obesity in db/db mice.

Objective: To assess the effect of long-term pharmacological inhibition of miR-21 in a model of metabolic syndrome and obesity.

Methods: Aged db/db mice were treated with locked nucleic acid-modified anti-miRs directed against miR-21 (LNA-21), control LNAs or PBS for 18 weeks. Cardiac function was assessed by echocardiography and the effect on body weight and white adipose tissue (WAT) was evaluated.

Results: MiR-21 expression was efficiently inhibited in the heart and WAT with no apparent liver toxicity or deterioration of kidney function. MiR-21 inhibition had no effect on cardiac hypertrophy as well as systolic and diastolic cardiac functions. However, levels of cardiac collagen 1 were modestly reduced in LNA-21 treated mice. MiR-21 inhibition reduced body weight, as well as adipocyte size and serum triglycerides were significantly decreased. The miR-21 targets TGFβ-receptor 2 (TGFBR2) and phosphatase and tensin homolog (PTEN) were derepressed in WAT of LNA-21 treated mice and Sprouty1 and 2 were increased after miR-21 inhibition.

Conclusions: Long-term treatment with LNA-21 is safe and efficiently suppresses miR-21 expression. Cardiac function was not affected. LNA-21 treatment led to a significant weight loss and reduces adipocyte size as well as derepression of the targets TGFRB2, PTEN, and Sprouty1 and 2.