Obesity is a disease caused by too much fat accumulation in the body, leading to other health problems such as cardiovascular disease, type 2 diabetes, and metabolic diseases. While diet and exercise are effective treatments, staying faithful to this strategy remains challenging. With the approval of glucagon-like peptide 1 agonists such as Ozempic and Zepbound, weight management via decrease in caloric intake has been achievable. However, these drugs have unwanted side effects. In this presentation, we will highlight our investigations on developing a complementary strategy of increasing energy expenditure using mitochondrial uncouplers. Mitochondrial uncouplers are small molecule protonophores that disrupt the proton motive force necessitating the increase in ‘nutrient burning’. The goal is to develop molecules that increase respiration without the need for exercise. The medicinal chemistry approach, assay development, and efficacy studies
in mice will be presented.