title: Therapeutic Inhibition of miR-33 Promotes Fatty Acid Oxidation but Does Not Ameliorate Metabolic Dysfunction in Diet-Induced Obesity.
abstract: OBJECTIVE
  miR-33 has emerged as an important regulator of lipid homeostasis. Inhibition of miR-33 has been demonstrated as protective against atherosclerosis; however, recent studies in mice suggest that miR-33 inhibition may have adverse effects on lipid and insulin metabolism. Given the therapeutic interest in miR-33 inhibitors for treating atherosclerosis, we sought to test whether pharmacologically inhibiting miR-33 at atheroprotective doses affected metabolic parameters in a mouse model of diet-induced obesity.
  
  
  RESULTS
  High-fat diet (HFD) feeding in conjunction with treatment of male mice with 10 mg/kg control anti-miR or anti-miR33 inhibitors for 20 weeks promoted equivalent weight gain in all groups. miR-33 inhibitors increased plasma total cholesterol and decreased serum triglycerides compared with control anti-miR, but not compared with PBS-treated mice. Metrics of insulin resistance were not altered in anti-miR33-treated mice compared with controls; however, respiratory exchange ratio was decreased in anti-miR33-treated mice. Hepatic expression of miR-33 targets Abca1 and Hadhb were derepressed on miR-33 inhibition. In contrast, protein levels of putative miR-33 target gene SREBP-1 or its downstream targets genes Fasn and Acc were not altered in anti-miR33-treated mice, and hepatic lipid accumulation did not differ between groups. In the adipose tissue, anti-miR33 treatment increased Ampk gene expression and markers of M2 macrophage polarization.
  
  
  CONCLUSIONS
  We demonstrate in a mouse model of diet-induced obesity that therapeutic silencing of miR-33 may promote whole-body oxidative metabolism but does not affect metabolic dysregulation. This suggests that pharmacological inhibition of miR-33 at doses known to reduce atherosclerosis may be a safe future therapeutic.
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Canada (D.K., L.R., M.G., D.B., R.J.G., K.J.R.); and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada (M.-E.H., K.J.R.).
authors.forename: Denuja
authors.initials: D
authors.lastname: Karunakaran
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Canada (D.K., L.R., M.G., D.B., R.J.G., K.J.R.); and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada (M.-E.H., K.J.R.).
authors.forename: Laura
authors.initials: L
authors.lastname: Richards
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Canada (D.K., L.R., M.G., D.B., R.J.G., K.J.R.); and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada (M.-E.H., K.J.R.).
authors.forename: Michele
authors.initials: M
authors.lastname: Geoffrion
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Canada (D.K., L.R., M.G., D.B., R.J.G., K.J.R.); and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada (M.-E.H., K.J.R.).
authors.forename: Danyk
authors.initials: D
authors.lastname: Barrette
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Canada (D.K., L.R., M.G., D.B., R.J.G., K.J.R.); and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada (M.-E.H., K.J.R.).
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Gotfrit
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Canada (D.K., L.R., M.G., D.B., R.J.G., K.J.R.); and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada (M.-E.H., K.J.R.).
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.affiliation: From the University of Ottawa Heart Institute, Ottawa, Canada (D.K., L.R., M.G., D.B., R.J.G., K.J.R.); and Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Canada (M.-E.H., K.J.R.). krayner@ottawaheart.ca.
authors.forename: Katey J
authors.initials: KJ
authors.lastname: Rayner
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D063993:Mitochondrial Trifunctional Protein, beta Subunit / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
chemical_list: D055372:AMP-Activated Protein Kinases; D064286:ATP Binding Cassette Transporter 1; D015415:Biomarkers; D001786:Blood Glucose; D002784:Cholesterol; D005227:Fatty Acids; D007328:Insulin; D035683:MicroRNAs; D063993:Mitochondrial Trifunctional Protein, beta Subunit; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; C577833:Abca1 protein, mouse; C550417:Mirn33 microRNA, mouse; C576207:Hadhb protein, mouse
keywords: cholesterol; diet, high-fat; microRNAs; obesity; therapeutics