Enoxacin induces oxidative metabolism and mitigates obesity by regulating adipose tissue miRNA expression

Abstract

MicroRNAs (miRNAs) have been implicated in oxidative metabolism and brown/beige adipocyte identity. Here, we tested whether widespread changes in miRNA expression promoted by treatment with the small-molecule enoxacin cause browning and prevent obesity. Enoxacin mitigated diet-induced obesity in mice, and this was associated with increased energy expenditure. Consistently, subcutaneous white and brown adipose tissues and skeletal muscle of enoxacin-treated mice had higher levels of markers associated with thermogenesis and oxidative metabolism. These effects were cell autonomous since they were recapitulated in vitro in murine and human cell models. In preadipocytes, enoxacin led to a reduction of miR-34a-5p expression and up-regulation of its target genes (e.g., Fgfr1, Klb, and Sirt1), thus increasing FGF21 signaling and promoting beige adipogenesis. Our data demonstrate that enoxacin counteracts obesity by promoting thermogenic signaling and inducing oxidative metabolism in adipose tissue and skeletal muscle in a mechanism that involves, at least in part, miRNA-mediated regulation.

Antibiotic Azithromycin inhibits brown/beige fat functionality and promotes obesity in human and rodents

“…Overall, these results suggested that the contribution of microbiota on AZI's metabolic influences was limited in our study. Interestingly, a recent report shows that the quinolone Enoxacin also exhibited direct effects on adipose tissues but not via microbiota 32 .…”

“…Previous reports have shown that bactericidal antibiotics, including Ciprofloxacin (quinolone), Ampicillin (β-lactam), and Kanamycin (aminoglycoside), lead to breakdown of tricarboxylic acid (TCA) cycle and electron transport chain (ETC) and consequently increased oxidative stresses in epithelial cells 30 . On the other hand, Enoxacin (another quinolone) induced intrinsic oxidative metabolism in a beneficial way, which resulted in enhanced TCA cycle, downregulation of mir-34a-5p and increased FGF21 signals, and eventually increased beige adipogenesis and ameliorated obesity 32 . Besides, recent work showed that Doxycycline (tetracyclines) prevented cell death and inflammation in severe mitochondria disease (MD) mutant cells and complex I deficiency (Ndufs4 -/- ) mice featuring Leigh syndrome by inducing mitohormetic response in neuronal system 73 .…”

Enoxacin ameliorates polycystic ovary syndrome by promoting the browning of white adipose tissue and restoring gut dysbiosis

“…Thermogenesis through exogenous activation, such as treatments of certain plant extracts (e.g., Rutin), cytokines (e.g., IL-22), may provide an alternative option ( Hu et al, 2017 ; Qi et al, 2019 ). A recent study has found that enoxacin induces thermogenesis and prevents obesity by regulating miR-34a-5p expression in adipose tissue ( Rocha et al, 2020 ). However, it is unknown whether these functions exist in DHEA-induced PCOS model and achieve the desired therapeutic effect of ameliorating reproductive and endocrine dysfunction.…”

“…Enoxacin is a broad-spectrum fluoroquinolone antibacterial agent that has been officially approved by the U.S. Food and Drug Administration for treating urinary tract infections ( Rocha et al, 2020 ). In addition, as a stimulator of RNA interference and microRNA activity, enoxacin also displays some biological effects on tumor growth or bone disease ( Melo et al, 2011 ; Cornaz-Buros et al, 2014 ; Liu et al, 2014 ; Zhao et al, 2022 ).…”

“…In addition, as a stimulator of RNA interference and microRNA activity, enoxacin also displays some biological effects on tumor growth or bone disease ( Melo et al, 2011 ; Cornaz-Buros et al, 2014 ; Liu et al, 2014 ; Zhao et al, 2022 ). A recent study revealed that enoxacin can increase adipose tissue thermogenesis and protect mice from dietary obesity and IR, which is achieved by a reduction of miR-34a-5p expression and upregulation of its downstream target genes ( Rocha et al, 2020 ). Given the essential role of adipose tissue in the development of PCOS, we suspect that enoxacin could alleviate reproductive disorders by improving adipose function in PCOS.…”