Axelrod 2021 EMBO Mol Med
|Axelrod CL, King WT, Davuluri G, Noland RC, Hall J, Hull M, Dantas WS, Zunica ER, Alexopoulos SJ, Hoehn KL, Langohr I, Stadler K, Doyle H, Schmidt E, Nieuwoudt S, Fitzgerald K, Pergola K, Fujioka H, Mey JT, Fealy C, Mulya A, Beyl R, Hoppel CL, Kirwan JP (2021) BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control. EMBO Mol Med 12:12088.|
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 (2021) EMBO Mol Med
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.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Obesity
Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue, Intact cells
Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: F, N, S, DQ, NS, ROX HRR: Oxygraph-2k