Weight Loss Drug Target May Work Without Causing Nausea

In recent years, the number of people receiving medical treatment for obesity has increased rapidly. Millions of people worldwide benefit from the GLP-1 hormone-based treatments such as Wegovy and Ozempic that help them lose weight. The treatment contributes to fewer people becoming part of the statistics for severe obesity globally.

But a side effect of the medication is vomiting and nausea. Side effects that make many people stop taking the drugs. Now, researchers at the University of Copenhagen have discovered a new powerful drug candidate that lowers appetite without loss of muscle mass or side effects like nausea and vomiting. And, unlike the current generation of treatments, the drug also increases the body’s energy expenditure – the capacity of the body to burn calories.

“While GLP-1-based therapies have revolutionized patient care for obesity and type 2 diabetes, safely harnessing energy expenditure and controlling appetite without nausea remain two holy grails in this field,” says Associate Professor Zach Gerhart-Hines from the NNF Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen. He adds:

“By addressing these needs, we believe our discovery will propel current approaches to make more tolerable, effective treatments accessible to millions more individuals.”

The new drug target, the so-called Neurokinin 2 Receptor (NK2R) also addresses another challenge. Studies show that treatments based on the GLP-1 hormone are less effective at lowering weight in people living with both obesity and type 2 diabetes – a group numbering more than 380 million people globally.

“While it remains unclear exactly why people living with both obesity and type 2 diabetes achieve less weight loss than individuals living with obesity, the need for improved treatment for this patient population is clear. This is where we believe NK2R agonism could make a meaningful impact.”

Burns energy and lowers appetite

Our weight is largely determined by the balance between the energy we consume and the amount of energy we expend. Eating more and burning less creates a positive energy balance leading to weight gain, while eating less and burning more creates a negative balance, resulting in weight loss. 

The current weight loss drugs tip the scales toward a negative energy balance by lowering appetite and the total calories a person consumes. But researchers have also recognised the potential on the other side of the equation – increasing the calories the body burns.  

This approach is especially relevant, given recent research that has shown that our bodies seem to be burning fewer calories at rest than they did a few decades ago. However, there are currently no clinically approved ways to safely increase energy expenditure, and few options are in development.

“This was the starting point when we decided to test the effect of activating the NK2R in mice. We identified the receptor through genetic screens that suggested NK2R played a role in maintaining energy balance and glucose control. Not only did activating the receptor safely increase calorie-burning, it also lowered appetite without any signs of nausea,” says PhD Student Frederike Sass from CBMR at the University of Copenhagen, and first author of the study. 

The study has been conducted in mice and non-human primates, which represents a big step towards clinical translation. That means that clinical tests in humans could be within the next 2 years, and that the drug could be ready within 5.

“The discovery could result in the next generation of drug therapies that bring more efficacious and tolerable treatments for the almost 400 million people globally who live with both type 2 diabetes and obesity,” says Zach Gerhart-Hines.

Reference: Sass F, Ma T, Ekberg JH, et al. NK2R control of energy expenditure and feeding to treat metabolic diseases. Nature. 2024. doi: 10.1038/s41586-024-08207-0

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