Small molecule mitochondrial uncouplers decrease oxidative efficiency resulting in increased nutrient oxidation and decreased mitochondrial reactive species production. Mitochondrial uncouplers have demonstrated anti-obesity effects in humans and protect from fatty liver disease in rodents. However, most mitochondrial uncouplers have limited use in the clinic due to their narrow therapeutic window between efficacy and toxicity. The on-target activity of mitochondrial uncouplers is the mitochondrial inner membrane; however, most uncouplers have unwanted off-target activity at other cellular membranes resulting in undesired effects including plasma membrane depolarization. Recently, we identified several new classes of mitochondrial uncouplers that do not depolarize the plasma membrane at concentrations needed to drive maximal mitochondrial respiration. Several molecules reverse obesity and insulin resistance in mice fed a Western Diet, and decrease non-alcoholic fatty liver disease activity score by 2 points in a mouse model of steatohepatitis. Importantly, these effects occur without decreased food intake or loss of lean body mass. These new mitochondrial uncouplers have a broad therapeutic window in vivo and may represent new therapeutic treatments for obesity and its related metabolic disorders.
KLH and WLS are co-founders of Continuum Biosciences and declare a commercial interest in the research.