Downregulation of elevated miR-34a in mice with diet-induced obesity reduced adiposity and promoted beige and brown fat formation by increasing FGF21 signaling and SIRT1 function.
Does lentivirus-mediated downregulation of miR-34a reduce adiposity and improve fat browning in mice with diet-induced obesity?
Downregulation of miR-34a promotes beige and brown fat formation and reduces adiposity in obese mice, identifying it as a potential therapeutic target for obesity-related diseases.
Brown fat generates heat through uncoupled respiration, protecting against hypothermia and obesity. Adult humans have brown fat, but the amounts and activities are substantially decreased in obesity, by unknown mechanisms. Here we show that elevated microRNA 34a (miR-34a) in obesity inhibits fat browning in part by suppressing the browning activators fibroblast growth factor 21 (FGF21) and SIRT1. Lentivirus-mediated downregulation of miR-34a in mice with diet-induced obesity reduced adiposity, improved serum profiles, increased the mitochondrial DNA copy number, and increased oxidative function in adipose tissue in both BALB/c and C57BL/6 mice. Remarkably, downregulation of miR-34a increased coexpression of the beige fat-specific marker CD137 and the browning marker UCP1 in all types of white fat, including visceral fat, and promoted additional browning in brown fat. Mechanistically, downregulation of miR-34a increased expression of the FGF21 receptor components, FGFR1 and βKL, and also that of SIRT1, resulting in FGF21/SIRT1-dependent deacetylation of PGC-1α and induction of the browning genes Ucp1, Pgc-1α, and Prdm16. Importantly, anti-miR-34a-mediated beneficial effects, including decreased adiposity, are likely from multiple tissues, since downregulation of miR-34a also improves hepatic FGF21 signaling and lipid oxidation. This study identifies miR-34a as an inhibitor of beige and brown fat formation, providing a potential target for treating obesity-related diseases.
Fu et al. (2014) studied Diet-induced obesity. Lentivirus-mediated antisense miR-34a vs. Scrambled control lentivirus was evaluated on Adiposity and fat browning markers (beige and brown fat formation). Downregulation of elevated miR-34a in mice with diet-induced obesity reduced adiposity and promoted beige and brown fat formation by increasing FGF21 signaling and SIRT1 function.