Regulation of cardiac miR-208a, an inducer of obesity, by rapamycin and nebivolol

Obesity (Silver Spring). 2015 Nov;23(11):2251-9. doi: 10.1002/oby.21227. Epub 2015 Sep 18.

Abstract

Objective: Resistance to obesity is observed in rodents and humans treated with rapamycin (Rap) or nebivolol (Neb). Because cardiac miR-208a promotes obesity, this study tested whether the modes of actions of Rap and Neb involve inhibition of miR-208a.

Methods: Mouse cardiomyocyte HL-1 cells and Zucker obese (ZO) rats were used to investigate regulation of cardiac miR-208a.

Results: Angiotensin II (Ang II) increased miR-208a expression in HL-1 cells. Pretreatment with an AT1 receptor (AT1R) antagonist, losartan (1 μM), antagonized this effect, whereas a phospholipase C inhibitor, U73122 (10 μM), and an NADPH oxidase inhibitor, apocynin (0.5 mM), did not. Ang II-induced increase in miR-208a was suppressed by Rap (10 nM), an inhibitor of nutrient sensor kinase mTORC1, and Neb (1 μM), a 3rd generation β-blocker that suppressed bioavailable AT1R binding of (125) I-Ang II. Thus, suppression of AT1R expression by Neb, inhibition of AT1R activation by losartan, and inhibition of AT1R-induced activation of mTORC1 by Rap attenuated the Ang II-induced increase in miR-208a. In ZO rats, Rap treatment (750 μg kg(-1) day(-1) ; 12 weeks) reduced obesity despite similar food intake, suppressed cardiac miR-208a, and increased cardiac MED13, a suppresser of obesity.

Conclusions: Rap and Neb suppressed cardiac miR-208a. Suppression of miR-208a and increase in MED13 correlated with attenuated weight gain despite leptin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Cells, Cultured
  • Gene Expression Regulation / drug effects
  • Male
  • Mediator Complex / physiology
  • Mice
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Nebivolol / pharmacology*
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology
  • Rats
  • Rats, Zucker
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sirolimus / pharmacology*
  • Weight Gain / drug effects
  • Weight Gain / genetics

Substances

  • MIRN208 microRNA, rat
  • Mediator Complex
  • MicroRNAs
  • Nebivolol
  • Angiotensin II
  • Sirolimus