Protein targets can act as a switch for obesity and anorexia

Weight and eating problems can result from various causes, including genetics, illness, eating or exercise habits and emotional distress.

Regardless of the disorder, the consequences can be severe and long lasting.

In the United States, dietary obesity has a prevalence of 40% and obesity increases the risk of other chronic diseases such as heart disease and diabetes.

Even though anorexia nervosa has a prevalence of 1%, it is the second-highest death rate of any mental illness.

Recently, Courage Therapeutics, a University of Michigan startup, received $7.8 million from Arsenal Bridge Ventures to develop medications for eating disorders and obesity.

The company’s two drug-development programs aim to target neural circuits in the brain known as the central melanocortin system.

Roger Cone, Ph.D., a professor of molecular and integrative physiology and member of Caswell Diabetes Institute, discusses how melanocortin receptors can be used to treat both obesity and anorexia.

What are the current therapies available for obesity?

Cone: Obesity has been extensively studied, in part due to the availability of mouse models.

The first obesity genes were discovered in mice, and they have helped researchers understand the molecular basis of feeding in humans.

As a result, for the first time, there are highly effective therapeutics for obesity.

The GLP-1 family of drugs, including Wegovy and Zepbound, causes an average weight loss of 15-20%. 

Our work shows that there'll be further improvements yet.

Are there any effective therapeutic strategies for anorexia?

Cone: The current measures mostly involve therapy, and there are no medications available.

The challenge with studying anorexia is that it has been underfunded by both the government and pharmaceutical industries.

We are slowly starting to understand the underlying genetic markers and identifying which molecules can be used as drug targets.

The other problem is that, unlike obesity, there is no accepted animal model. Therefore, any drug we have must be tested directly in patients.

Currently, drugs for anorexia are tested in compassionate-use trials for severely ill people who have been hospitalized.

It's important to thoroughly test the safety of these drugs before we can use them in a larger population.

How does the melanocortin system work?

Cone: We have been studying melanocortin for more than three decades.

We discovered that two receptor proteins, melanocortin 3 receptor and melanocortin 4 receptor, play an important role in regulating food intake.

These receptors act like a switch—if you toggle it one way it inhibits food intake and the other way stimulates eating.

Our company is developing drugs that will target the melanocortin circuits in both obesity and anorexia.

We expect to move forward with clinical trials within the next two years.

Can these drugs work in combination with GLP-1 medications?

Cone: Drugs in the GLP-1 class are satiety agents, meaning they trick the brain into thinking that you're full.

That feeling reduces food intake and leads to weight loss.

However, data from multiple labs has shown that even GLP-1 drugs work through the melanocortin circuits in the brain.

We have previously shown that if we pre-sensitize these melanocortin circuits, we can enhance the activity of the GLP-1 drugs by as much as fivefold.

Additionally, this increase in effectiveness does not affect the part of the brain which causes the feeling of nausea.

Together, our results suggest that we can help more patients achieve weight loss, especially those who experience nausea when they take GLP-1 drugs and are not able to continue with treatment.

Tech transfer(s)/Conflict(s) of interest: Cone and the University of Michigan are shareholders in Courage Therapeutics.

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