Pharmacologic approaches to the treatment of obesity

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

Obesity is a huge and increasing medical problem, with inadequate therapeutic options. One approach to the treatment of obesity is long-term pharmacotherapy. Drugs currently approved in the United States include orlistat, phentermine/topiramate, bupropion/naltrexone, and setmelanotide. More recently, liraglutide, semaglutide, and tirzepatide have been approved and revolutionized the treatment of obesity. It is important to understand how these agents work. Progress in FY2024-25 includes the following: Mice are not simply small humans. Because mice are used widely to study diabetes and obesity, understanding their thermal biology is critical to translating observations from mice to humans. In humans, the heat needed to maintain body temperature is virtually all created as a byproduct of metabolic processes. People generally live in a thermoneutral zone, a 10C range of ambient temperatures over which core body temperature is maintained without increasing metabolic rate. In contrast, mice typically live below thermoneutrality. At room temperature (20-22C) about one third of food intake is used to generate heat. We are undertaking a range of quantitative analyses to understand the contributors to mouse energy expenditure. These results inform how mice can be used to model human obesity physiology and drug development. We are currently using this new knowledge about thermoneutrality in mice to explore its implications in energy homeostasis. Examples of recent work include demonstration of the dissociation of sleep/wake from the light/dark phases in mice, that housing mice at 22C vs 30C does not improve prediction of human anti-obesity efficacy, that GLP-1 agonists prevent metabolic adaptation, and GPR45's possible role in energy homeostasis.