Scientists at the University of Copenhagen have discovered a new weight loss drug target that reduces appetite, increases energy expenditure and improves insulin sensitivity without causing nausea or muscle loss. The discovery was reported in the journal Nature and could lead to a new treatment for millions of people with both obesity and type 2 diabetes who do not respond well to current treatments.
Millions of people around the world benefit from slimming drugs based on the incretin hormone GLP-1. These drugs also improve kidney function, reduce the risk of fatal cardiac events, and are linked to protection against neurodegeneration. However, many people stop taking the drugs because of common side effects, such as nausea and vomiting. Studies also show that incretin-based treatments like Wegovy and Mounjaro are much less effective at reducing weight in people living with both obesity and type 2 diabetes – a group that numbers more than 380 million people worldwide.
In a study published in Naturescientists from the University of Copenhagen describe a powerful new drug candidate that reduces appetite without muscle loss or side effects such as nausea and vomiting. And, unlike the current generation of treatments, the drug also increases the body’s energy expenditure – the body’s ability to burn calories.
While GLP-1-based therapies have revolutionized patient care for obesity and type 2 diabetes, safely utilizing energy expenditure and controlling appetite without nausea remain two Holy Grails in this field. By addressing these needs, we believe our discovery will advance current approaches to make more tolerable, effective treatments accessible to millions more people.”
Zach Gerhart-Hines, Associate Professor from the NNF Foundation Center for Basic Metabolic Research (CBMR), University of Copenhagen
NK2R activation reduces body weight and reverses diabetes
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 that leads to weight gain, while eating less and burning more creates a negative energy balance, resulting in weight loss.
The current generation of incretin-based therapies tip the scales toward a negative energy balance by reducing a person’s appetite and total calories consumed. But scientists have also recognized the possibility of the other side of the equation – increasing the calories the body burns. This approach is especially important given recent research that has shown that our bodies seem to burn fewer calories at rest than they have in decades. However, there are currently no clinically approved ways to safely increase energy expenditure, and few options are under development.
This was the starting point when scientists at the University of Copenhagen decided to test the effect of activating the neurokinin 2 receptor (NK2R) in mice. The Gerhart-Hines team identified the receptor through genetic screens that suggested NK2R played a role in maintaining energy balance and glucose control. They were surprised by the results of the studies – not only did activating the receptor safely increase calorie burning, but it also reduced appetite without signs of nausea.
Further studies in non-human primates with type 2 diabetes and obesity showed that NK2R activation reduced body weight and reversed diabetes by increasing insulin sensitivity and lowering blood sugar, triglycerides and cholesterol.
“One of the biggest hurdles in drug development is translation between mice and humans. That’s why we were excited that the benefits of NK2R agonism translated into diabetic and obese nonhuman primates, which represents a big step toward clinical translation,” says PhD Student Frederike. Sass from CBMR at the University of Copenhagen and first author of the study.
The discovery could lead to the next generation of drug therapies that will bring more effective and tolerable treatments to the nearly 400 million people worldwide living with both type 2 diabetes and obesity. The University of Copenhagen holds the patent rights to target NK2R. To date, research from the Gerhart-Hines laboratory has led to the creation of three biotech companies – Embark Biotech, Embark Laboratories and Incipiam Pharma. In 2023, Embark Biotech was acquired by Novo Nordisk to develop next-generation therapies for cardiometabolic diseases.
