How to reduce the side effects of obesity drugs?

A study published in the journal Nature describes two different neural circuits that regulate different effects of the same drug.

In recent years, there has been great progress in the treatment of type 2 diabetes with the advent of drugs that use semaglutide as an active ingredient, a peptide similar to the hormone glucagon-1 or GLP-1, which plays a balancing role. The role of insulin in blood sugar balance. When blood sugar levels drop, glucagon causes the liver release glucose and when it increases, more insulin is produced, which is responsible for reducing the excess. In addition, semaglutide causes a noticeable decrease in appetite, which made Ozempic, one of the drugs produced with this active ingredient, successful.

Science Magazine called these obesity drugs the greatest scientific achievement of 2023. anti-obesity drugs, They also have side effects, and it involves balancing the physiological connection between the feeling of fullness after eating and the neurological control of nausea.

Now, by separating the therapeutic benefits from the side effects of these drugs, researchers from Monell Chemical Senses Centerr (USA) discovered a population of neurons in the brain that controls food intake without causing nausea in an animal model.

The study, published in the journal Naturedescribes two different neural circuits that regulate different effects of the same drug. The drugs studied are among the most effective weight-loss agents available, known as long-acting glucagon-like peptide 1 receptor (GLP1R) agonists, which initiate neurochemical reactions through receptors expressed throughout the body.

One of the most effective and popular GLP1-based drugs, called semaglutide and sold under the brand names Ozempic and Wegovy, has shown impressive weight loss results in clinical trials. According to World Health Organization, in 2022, 1 out of 8 people People all over the world live with obesity, so developing such drugs is of paramount importance.

“One of the barriers to pharmacological treatment of obesity is side effects like nausea and vomiting,” recalls lead author Dr. Amber L. Alhadeff, a research fellow at Monell. “It wasn’t clear to us whether these side effects were related to the weight loss effect or necessary for it.”

To find out, Monell’s team examined the brain circuits that link feelings of fullness after eating with those that cause people to avoid eating because they feel sick. The researchers found that neurons in the hindbrain mediate both effects of these anti-obesity drugs, and, surprisingly, they also found that the individual neurons that mediate feelings of fullness and nausea are distinct.

Two-photon imaging of hindbrain GLP1R neurons in living mice revealed that most individual neurons are tuned to respond to stimuli that are either nutritious or aversive, but not both. Moreover, the study found that GLP1R neurons in a part of the hindbrain called the area postrema respond more to aversive stimuli, while GLP1R neurons in another area called the nucleus solitarius are biased toward nutritious stimuli.

“Developing experimental anti-obesity drugs that selectively activate this population could promote weight loss and prevent “unpleasant side effects,” Alhadeff says.In fact, the authors say, the concept of separating therapeutic and side effects at the level of neural circuits could theoretically be applied to any drug with side effects.