A New Strategy for Diabetes and Obesity: Exercise in a Pill

Scientists working to develop the potential of nuclear receptors

Researchers at Saint Louis University in Missouri plan to tackle the twin epidemics of diabetes and obesity by tapping into the potential of two nuclear receptors that control muscle metabolism. The scientists are working to optimize two promising drug compounds, moving a step closer toward capturing the benefits of exercise in pill form.

In previous studies conducted at the university, a drug that targets REV-ERB—a receptor linked to muscle metabolism—appeared to act as an exercise mimic. Genetic studies also suggested that another receptor, ERR, might be a good target for the development of exercise-mimetic drugs.

“If you exercise, it’s effectively a treatment for diabetes and obesity as you increase the metabolic rate of muscle,” said investigator Thomas Burris, PhD, a pharmacologist. “You develop a more-efficient muscle. That’s what you get from exercise. You develop more endurance, and that is good for your metabolic function. 

“Our drug compounds are doing similar things. They make muscles look like they’re exercising, turning on the genes that get activated during exercise, even if no exercise is happening.”

Burris and his team were the first to show that a synthetic agonist for REV-ERB caused weight loss and improved metabolic function in animals.

One of the challenges in their current study is to prevent the drug from crossing the blood–brain barrier. That is the opposite of the problem that drug designers usually face. In addition to addressing the blood–brain barrier issue, Burris and his co-workers are looking to optimize the REV-ERB compound in other ways, including testing for toxic properties and developing once-a-day dosing.

In another study, the researchers hope to develop compounds that target the ERR receptor. 

“We’ve designed some agonists to see what their effect is,” said Dr. Burris’ colleague, chemist John Walker, PhD. “Most of the data suggest that more ERR is better [and] the most useful in terms of muscle metabolism.”

In addition to showing promise for obesity and diabetes, the study will examine how improvements to muscle metabolism may affect muscular dystrophy. 

Source: Saint Louis University; March 23, 2017.