Join Christopher Axelrod and Sander Kooijman, PhD for a discussion on their research into combatting obesity using various new therapies.
Targeting Mitochondrial Bioenergetics for the Treatment of Obesity and Type 2 Diabetes
Obesity is a leading cause of morbidity and mortality worldwide. Despite this, current pharmacological strategies for the treatment of obesity remain largely ineffective at achieving long‐term weight control. This is due, in part, to the difficulty of identifying tolerable and efficacious small molecules or biologics capable of regulating systemic nutrient homeostasis. This research demonstrates that a mitochondrially targeted Furazano[3,4-b]Pyrazine named BAM15 stimulates energy expenditure as well as enhances nutrient metabolism to protect against diet‐induced obesity. C57BL/6J mice treated with BAM15 were entirely resistant to diet-induced 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 and sustained activation of AMP-activated protein kinase. Collectively, these data establish pre‐clinical efficacy for mitochondrially targeted protonophores as a pharmacological approach in the treatment of obesity and related diseases.
Circadian (Dys)regulation of Energy Metabolism
Sander Kooijman, PhD
Disruption of circadian (~24 hour) rhythms is associated with increased risk of obesity, diabetes and cardiovascular disease. Sexual dimorphism has been identified in the response to mimicked shift work; male mice were more prone to develop obesity, whilst female mice exhibited impaired postprandial lipid and glucose clearance from the circulation. Most likely as a result of this dietary spillover, mimicked shift work in female APOE*3-Leiden.CETP mice, a unique model for human-like lipoprotein metabolism, resulted in increased atherosclerosis development characterized by oxidative stress in the vasculature. Current studies are evaluating how to prevent shift work-induced cardiometabolic problems. Understanding of the circadian (dys)regulation of energy metabolism through these studies also comes with the opportunity to maximize the effectiveness of therapy, so-called ‘chronotherapy’. This presentation will address insights in the underlying pathophysiology obtained from studies in mice.
Key Topics Include:
- Obesity is a chronic disease with limited treatment options that achieve long term weight control
- Systemic mitochondrial uncoupling prevents weight gain without altering food intake and improves glucose metabolism independent of body weight
- Mitochondrial-targeted drugs such as BAM15 may have clinical utility in the treatment of obesity and related diseases
- Mimicked shift work resulted in obesity in male mice and poor blood glucose clearance in female mice
- Understanding the circadian regulation of energy metabolism provides an opportunity to maximize the effectiveness of chronotherapy
Director of Translational Services
Integrated Physiology and Molecular Medicine Laboratory
Pennington Biomedical Research Center
Leiden University Medical Center