Scientists at the University of Copenhagen have discovered a new weight loss drug target, neurokinin 2 receptor (NK2R), that reduces appetite, increases energy expenditure and improves insulin sensitivity without causing nausea or loss of muscle mass. The discovery could lead to a new therapy for millions of people with both obesity and type 2 diabetes who do not respond well to current treatments.
"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,” explained Associate Professor, Zach Gerhart-Hines from the NNF Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen. “By addressing these needs, we believe our discovery will propel current approaches to make more tolerable, effective treatments accessible to millions more individuals.”
The current generation of incretin-based therapies tip the scales toward a negative energy balance by lowering appetite and the total calories a person consumes. However, scientists 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 scientists at the University of Copenhagen decided to test the effect of activating the NK2R in mice. The Gerhart-Hines Group 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. Further studies in non-human primates with type 2 diabetes and obesity showed that NK2R activation lowered body weight and reversed their 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. This is why we were excited that the benefits of NK2R agonism translated to diabetic and obese nonhuman primates, which represents a big step towards clinical translation," added PhD student, Frederike Sass from CBMR at the University of Copenhagen, and first author of the study.
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.
The University of Copenhagen holds the patent rights for targeting NK2R. To date, research by the Gerhart-Hines lab 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 therapeutics for cardiometabolic disease.
The findings were reported in the paper, ‘NK2R control of energy expenditure and feeding to treat metabolic diseases’, published in Nature. To access this paper, please click here
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