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BAM15-mediated mitochondrial uncoupling protects against obesity and improves glycemic control
Christopher L Axelrod1,2,3, William T King1,2, Gangarao Davuluri1,4
1Integrated Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
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.
Insights
BAM15, a novel molecule, effectively combats diet-induced obesity by boosting energy expenditure and improving metabolism. This research highlights BAM15 as a promising therapeutic for obesity and related metabolic diseases.
Area of Science:
- Metabolic diseases
- Pharmacology
- Mitochondrial biology
Background:
- Obesity is a major global health issue with limited effective long-term treatments.
- Current obesity treatments struggle with efficacy and long-term weight management.
- Developing novel therapeutics targeting nutrient homeostasis is crucial.
Purpose of the Study:
- To investigate the anti-obesity effects of BAM15, a mitochondrially targeted protonophore.
- To characterize the metabolic benefits of BAM15 in preclinical models.
- To evaluate BAM15 as a potential pharmacological treatment for obesity.
Main Methods:
- In vitro studies assessing mitochondrial respiration and insulin action.
- In vivo studies using C57BL/6J mice fed a high-fat diet.
- Analysis of body composition, glycemic control, and metabolic parameters.
Main Results:
- BAM15 enhanced mitochondrial respiratory kinetics and improved insulin sensitivity in vitro.
- Mice treated with BAM15 showed resistance to diet-induced weight gain.
- BAM15 improved body composition and glycemic control independently of weight loss, targeting lipid-rich tissues.
Conclusions:
- BAM15 demonstrates significant pre-clinical efficacy against diet-induced obesity.
- BAM15 stimulates energy expenditure and improves glucose and lipid metabolism.
- BAM15 represents a promising pharmacological strategy for obesity and associated metabolic disorders.
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