BAM15‐mediated mitochondrial uncoupling protects against obesity and improves glycemic control

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.

Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH

“…Indeed, hyperinsulinemic-euglycemic clamp studies demonstrated that BAM15 enhanced insulin sensitivity in skeletal muscle and white adipose tissue [ 111 ]. In support of this, oral dosing of BAM15 (∼85 mg/kg/day) was independently shown to prevent diet-induced obesity and improve glycemic control through alterations in whole-body energy expenditure, reduced adiposity, and AMPK-mediated suppression of WAT lipogenesis [ 112 ], supporting a crucial role of adipose tissue in mediating BAM15's beneficial effects. Interestingly, previous studies did not demonstrate an adipose-targeted depot for BAM15-mediated uncoupling [ 111 ]; however, differences in dose routes and pharmacokinetic study designs could explain these discrepancies.…”

CRISPR/Cas9-engineered Drosophila knock-in models to study VCP diseases

“…Oxidative phosphorylation (OXPHOS) and electron transfer (ET) capacity of permeabilized flight muscle was determined by high-resolution respirometry (Oroboros O2k; Innsbruck, Austria) as described previously (Simard et al 2018;Axelrod et al 2020). Briefly, 2-3 flies aged 3-7 or 30-35 days were sedated by cold exposure at 4°C for 7-10 min.…”

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

“…The use of regulators of oxidative stress in the comprehensive treatment of diabetes was found to maintain the structural and functional integrity of mitochondria. It has been shown that the mitochondrial-targeted antioxidants MitoTEMPO, MitoQ, BAM15, C12TPP, and CoQ10 partially prevent the ROS-induced disorders in oxidative phosphorylation and ultrastructure of mitochondria in animal models of obesity and insulin resistance [ 38 , 139 , 140 , 141 , 142 ]. Currently, the positive effects of CoQ10 and resveratrol as antidiabetic drugs have been demonstrated in most clinical trials [ 143 ].…”