Background

Current pharmacologic strategies for the treatment of obesity are ineffective at achieving long-term weight control. This is due, in part, to difficulties in identifying tolerable and efficacious small molecules and biologics capable of regulating systemic nutrient homeostasis. Herein, we tested the hypothesis that BAM15, a mitochondrially targeted small molecule, could upregulate whole body energy expenditure and nutrient metabolism to protect against diet induced obesity (DIO).

Methods

10 week old male DIO C57B6/J mice were randomized to 3 weeks of control (60% HFD) or BAM15 (60% HFD + 0.01% w/w BAM15) diet. Body weight and temperature, as well as food intake, were measured daily throughout the study period. At the end of treatment, animals were assessed for body composition (NMR), energy expenditure (continuous indirect calorimetry), and glucose tolerance (IPGTT). Gastrocnemius muscle was collected at harvest and assessed for mitochondrial ultrastructure and content (Cryo-EM), oxidative phosphorylation (mtOXPHOS), fatty acid oxidation ([U-13C]palmitate), histological analyses (H&E), protein expression (Western blot), and transcriptomics (RNAseq).

Results

BAM15 treated animals were resistant to diet-induced weight gain, displayed reduced body fat accrual, enhanced glucose clearance, and glycemic control. Reduced body weight in BAM15 treated animals was attributable to increased whole body energy expenditure, mediated in part by elevated skeletal muscle oxidation of palmitic acid. Notably, BAM15 did not alter food intake, had no acute or chronic effect on core body temperature, and did not result in any observable histopathological features of previous generation protonophores.

Conclusions

We provide the first evidence of BAM15 as a tolerable and efficacious mitochondrially targeted small molecule for the treatment of obesity and associated comorbidities.