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. |
Christopher L Axelrod, William T King, Gangarao Davuluri, Robert C Noland, Jacob Hall, Michaela Hull, Wagner S Dantas, Elizabeth RM Zunica, Stephanie J Alexopoulos, Kyle L Hoehn, Ingeborg Langohr, Krisztian Stadler, Haylee Doyle, Eva Schmidt, Stephan Nieuwoudt, Kelly Fitzgerald, Kathryn Pergola, Hisashi Fujioka, Jacob T Mey, Ciaran Fealy, Anny Mulya, Robbie Beyl, Charles L Hoppel, John P Kirwan (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. • Keywords: AMPK, BAM15, Mitochondria, Obesity, Type 2 diabetes • Bioblast editor: Reiswig R
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Mouse
Tissue;cell: Skeletal muscle
Preparation: Intact cells
Coupling state: ROUTINE, OXPHOS, ET
Pathway: F, N, S, NS, ROX
HRR: Oxygraph-2k
2021-07
