An Estrogen-Related Receptor Agonist Exercise Mimetic Performs Well in Mice

Researchers here demonstrate in mice an effective approach to mimicking some of the adaptive responses to exercise, and sustaining those responses over time. Exercise mimetics have undergone a sedate pace of development in comparison to the larger body of work on calorie restriction mimetics, intended to mimick some of the sweeping changes to metabolism that occur at low nutrient levels, and the field isn't yet as well established. Still, some interesting lines of work have emerged, such as the program noted here.

The new drug, known as SLU-PP-332, doesn't affect appetite or food intake. Nor does it cause mice to exercise more. Instead, the drug boosts a natural metabolic pathway that typically responds to exercise. In effect, the drug makes the body act like it is training for a marathon, leading to increased energy expenditure and faster metabolism of fat in the body. The drug leads obese mice to lose weight by convincing the body's muscles that they are exercising more than they really are, boosting the animals' metabolism. It also increases endurance, helping mice run nearly 50% further than they could before. All without the mice lifting a paw.

"This compound is basically telling skeletal muscle to make the same changes you see during endurance training. When you treat mice with the drug, you can see that their whole body metabolism turns to using fatty acids, which is very similar to what people use when they are fasting or exercising. And the animals start losing weight."

The new drug targets a group of proteins in the body known as estrogen-related receptors (ERRs), which are responsible for activating some of the most important metabolic pathways in energy-gobbling tissues like muscles, the heart, and the brain. The ERRs are more active when people exercise, but they have proven difficult to activate with drugs. In another paper published in March, the researchers reported that they had successfully designed SLU-PP-332 to boost activity of the ERRs. They also observed that the compound allowed normal-weight mice to run for 70% longer and 45% further than mice not receiving the drug. In their latest research, the team tested the drug on obese mice. Treating obese mice twice a day for a month caused them to gain 10 times less fat than untreated mice and lose 12% of their body weight. Yet the mice kept eating the same amount of food and didn't exercise any more.