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BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control.
Axelrod, Christopher L; King, William T; Davuluri, Gangarao; Noland, Robert C; Hall, Jacob; Hull, Michaela; Dantas, Wagner S; Zunica, Elizabeth Rm; Alexopoulos, Stephanie J; Hoehn, Kyle L; Langohr, Ingeborg; Stadler, Krisztian; Doyle, Haylee; Schmidt, Eva; Nieuwoudt, Stephan; Fitzgerald, Kelly; Pergola, Kathryn; Fujioka, Hisashi; Mey, Jacob T; Fealy, Ciaran; Mulya, Anny; Beyl, Robbie; Hoppel, Charles L; Kirwan, John P.
Afiliación
  • Axelrod CL; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • King WT; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Davuluri G; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Noland RC; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Hall J; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Hull M; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Dantas WS; Sarcopenia and Malnutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Zunica ER; Skeletal Muscle Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Alexopoulos SJ; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Hoehn KL; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Langohr I; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Stadler K; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Doyle H; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Schmidt E; Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA.
  • Nieuwoudt S; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
  • Fitzgerald K; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia.
  • Pergola K; Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, LA, USA.
  • Fujioka H; Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Mey JT; Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Fealy C; Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Mulya A; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Beyl R; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Hoppel CL; Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • Kirwan JP; Department of Translational Services, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
EMBO Mol Med ; 12(7): e12088, 2020 07 07.
Article en En | MEDLINE | ID: mdl-32519812
ABSTRACT
Obesity is a leading cause of preventable death worldwide. Despite this, current strategies for the treatment of obesity remain ineffective at achieving long-term weight control. This is due, in part, to difficulties in identifying tolerable and efficacious small molecules or biologics capable of regulating systemic nutrient homeostasis. Here, we demonstrate that BAM15, a mitochondrially targeted small molecule protonophore, stimulates energy expenditure and glucose and lipid metabolism to protect against diet-induced obesity. Exposure to BAM15 in vitro enhanced mitochondrial respiratory kinetics, improved insulin action, and stimulated nutrient uptake by sustained activation of AMPK. C57BL/6J mice treated with BAM15 were resistant to weight gain. Furthermore, BAM15-treated mice exhibited improved body composition and glycemic control independent of weight loss, effects attributable to drug targeting of lipid-rich tissues. We provide the first phenotypic characterization and demonstration of pre-clinical efficacy for BAM15 as a pharmacological approach for the treatment of obesity and related diseases.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Desacopladores / Control Glucémico / Glucosa / Mitocondrias / Obesidad Límite: Animals Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Desacopladores / Control Glucémico / Glucosa / Mitocondrias / Obesidad Límite: Animals Idioma: En Revista: EMBO Mol Med Asunto de la revista: BIOLOGIA MOLECULAR Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos