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

Enoxacin mitigates obesity by inducing fat and muscle energy metabolism independently of its antibiotic function. 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.

[1]  B. Emanuelli,et al.  CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice , 2020, Science Translational Medicine.

[2]  D. Ferrucci,et al.  The influence of hypertensive environment on adipose tissue remodeling measured by fluorescence lifetime imaging in spontaneously hypertensive rats , 2020, Molecular and Cellular Endocrinology.

[3]  A. Mardinoğlu,et al.  Mature Human White Adipocytes Cultured under Membranes Maintain Identity, Function, and Can Transdifferentiate into Brown-like Adipocytes. , 2019, Cell reports.

[4]  No-Joon Song,et al.  Mechanisms underlying UCP1 dependent and independent adipocyte thermogenesis , 2018, Obesity reviews : an official journal of the International Association for the Study of Obesity.

[5]  K. Massirer,et al.  Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis , 2018, Redox biology.

[6]  M. Mori,et al.  Crotamine induces browning of adipose tissue and increases energy expenditure in mice , 2018, Scientific Reports.

[7]  J. Marchant.  When antibiotics turn toxic , 2018, Nature.

[8]  S. Koo,et al.  Hepatic Crtc2 controls whole body energy metabolism via a miR-34a-Fgf21 axis , 2017, Nature Communications.

[9]  Jan Nedergaard,et al.  Optimal housing temperatures for mice to mimic the thermal environment of humans: An experimental study , 2017, Molecular metabolism.

[10]  M. Mori,et al.  Shortcuts to a functional adipose tissue: The role of small non-coding RNAs , 2017, Redox biology.

[11]  Nathan S. Abell,et al.  Click Quantitative Mass Spectrometry Identifies PIWIL3 as a Mechanistic Target of RNA Interference Activator Enoxacin in Cancer Cells. , 2017, Journal of the American Chemical Society.

[12]  M. Caslake,et al.  miR‐34a−/− mice are susceptible to diet‐induced obesity , 2016, Obesity.

[13]  C. Kahn,et al.  Fat-specific Dicer deficiency accelerates aging and mitigates several effects of dietary restriction in mice , 2016, Aging.

[14]  J. Greenfield,et al.  Brown Adipose Tissue Exhibits a Glucose-Responsive Thermogenic Biorhythm in Humans. , 2016, Cell metabolism.

[15]  S. Hammond,et al.  Dysregulated miRNA biogenesis downstream of cellular stress and ALS‐causing mutations: a new mechanism for ALS , 2015, The EMBO journal.

[16]  Jennifer A. Doudna,et al.  Dicer-TRBP complex formation ensures accurate mammalian microRNA biogenesis. , 2015, Molecular cell.

[17]  A. Doria,et al.  Activation of human brown adipose tissue by a β3-adrenergic receptor agonist. , 2015, Cell metabolism.

[18]  Kinyui A. Lo,et al.  MicroRNAs Are Required for the Feature Maintenance and Differentiation of Brown Adipocytes , 2014, Diabetes.

[19]  Yoosik Kim,et al.  Deletion of human tarbp2 reveals cellular microRNA targets and cell-cycle function of TRBP. , 2014, Cell reports.

[20]  J. Kemper,et al.  MicroRNA 34a Inhibits Beige and Brown Fat Formation in Obesity in Part by Suppressing Adipocyte Fibroblast Growth Factor 21 Signaling and SIRT1 Function , 2014, Molecular and Cellular Biology.

[21]  C. Kahn,et al.  Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. , 2014, The Journal of clinical investigation.

[22]  I. Rustenbeck,et al.  Effect of fluoroquinolones on mitochondrial function in pancreatic beta cells. , 2014, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[23]  Neil R. Smalheiser,et al.  Enoxacin Elevates MicroRNA Levels in Rat Frontal Cortex and Prevents Learned Helplessness , 2014, Front. Psychiatry.

[24]  Rachel M. Perron,et al.  Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. , 2014, Cell metabolism.

[25]  Xiaoling Li,et al.  Elevated microRNA‐34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT , 2013, Aging cell.

[26]  J. Collins,et al.  Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells , 2013, Science Translational Medicine.

[27]  H. Fröhlich,et al.  miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit , 2013, Nature Communications.

[28]  C. Palmeira,et al.  Enoxacin inhibits growth of prostate cancer cells and effectively restores microRNA processing , 2013, Epigenetics.

[29]  Y. Mishina,et al.  Brown Fat Paucity Due to Impaired BMP Signaling Induces Compensatory Browning of White Fat , 2013, Nature.

[30]  M. Stoffel,et al.  MyomiR-133 regulates brown fat differentiation through Prdm16 , 2012, Nature Cell Biology.

[31]  C. Kahn,et al.  Role of microRNA processing in adipose tissue in stress defense and longevity. , 2012, Cell metabolism.

[32]  B. Spiegelman,et al.  Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human , 2012, Cell.

[33]  A. Kandasamy,et al.  Levofloxacin-induced acute anxiety and insomnia , 2012, Journal of neurosciences in rural practice.

[34]  Shingo Kajimura,et al.  PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. , 2012, Cell metabolism.

[35]  S. Kliewer,et al.  Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ , 2012, Proceedings of the National Academy of Sciences.

[36]  B. Spiegelman,et al.  FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. , 2012, Genes & development.

[37]  B. Spiegelman,et al.  A PGC1α-dependent myokine that drives browning of white fat and thermogenesis , 2012, Nature.

[38]  H. Lodish,et al.  MiR-193b-365, a brown fat enriched microRNA cluster, is essential for brown fat differentiation , 2011, Nature cell biology.

[39]  H. Inoue,et al.  Effect of Enoxacin, Felbinac, and Sparfloxacin on Fatty Acid Metabolism and Glucose Concentrations in Rat Tissues , 2011, International journal of toxicology.

[40]  George A Calin,et al.  Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing , 2011, Proceedings of the National Academy of Sciences.

[41]  F. Villarroya,et al.  Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue* , 2011, The Journal of Biological Chemistry.

[42]  Oliver T. Bruns,et al.  Brown adipose tissue activity controls triglyceride clearance , 2011, Nature Medicine.

[43]  A. Cypess,et al.  The role and importance of brown adipose tissue in energy homeostasis , 2010, Current opinion in pediatrics.

[44]  Qing Yang,et al.  Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway , 2010, Proceedings of the National Academy of Sciences.

[45]  David W. Taylor,et al.  A Novel miRNA Processing Pathway Independent of Dicer Requires Argonaute2 Catalytic Activity , 2010, Science.

[46]  G. Hannon,et al.  A dicer-independent miRNA biogenesis pathway that requires Ago catalysis , 2010, Nature.

[47]  R. Ketting,et al.  The role of small non-coding RNAs in genome stability and chromatin organization , 2010, Journal of Cell Science.

[48]  V. Kim,et al.  Regulation of microRNA biogenesis , 2014, Nature Reviews Molecular Cell Biology.

[49]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[50]  C. Kahn,et al.  Sex and Depot Differences in Adipocyte Insulin Sensitivity and Glucose Metabolism , 2009, Diabetes.

[51]  Z. Xi,et al.  Enhancement of RNAi by a small molecule antibiotic enoxacin , 2008, Cell Research.

[52]  Z. Paroo,et al.  A small molecule enhances RNA interference and promotes microRNA processing , 2008, Nature Biotechnology.

[53]  Moshe Oren,et al.  Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. , 2007, Molecular cell.

[54]  B. Cannon,et al.  UCP1 is essential for adaptive adrenergic nonshivering thermogenesis. , 2006, American journal of physiology. Endocrinology and metabolism.

[55]  R. Kesterson,et al.  Deletion of PPARγ in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[56]  J. Himms-Hagen,et al.  CL316,243 and Cold Stress Induce Heterogeneous Expression of UCP1 mRNA and Protein in Rodent Brown Adipocytes , 2002, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[57]  StéphaneMoniotte,et al.  Upregulation of β3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium , 2001 .

[58]  J. Balligand,et al.  Upregulation of &bgr;3-Adrenoceptors and Altered Contractile Response to Inotropic Amines in Human Failing Myocardium , 2001, Circulation.

[59]  P. Puigserver,et al.  A Cold-Inducible Coactivator of Nuclear Receptors Linked to Adaptive Thermogenesis , 1998, Cell.

[60]  Kyuhyun Wang,et al.  Hemodynamic Predictors of Myocardial Oxygen Consumption During Static and Dynamic Exercise , 1974, Circulation.

[61]  M. Ruth.  A PGC1–α–dependent myokine that drives brown–fat–like development of white fat and thermogenesis , 2012 .

[62]  C. Arenz,et al.  A fluorescence probe for assaying micro RNA maturation. , 2008, Bioorganic & medicinal chemistry.

[63]  M. Kawamura,et al.  Effect of fluoroquinolones on plasma glucose levels in fasted and glucose-loaded mice , 2006, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[64]  R. Kesterson,et al.  Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[65]  H. Laborit,et al.  [Experimental study]. , 1958, Bulletin mensuel - Societe de medecine militaire francaise.