Scientists at the University of Copenhagen have identified a weight loss drug target, neurokinin 2 receptor (NK2R), which they suggest could lead to a new therapeutic strategy for millions of people with both obesity and type 2 diabetes (T2D) who do not respond well to current treatments. The team in addition developed an NK2R agonist candidate which, when tested in different animal models, was found to reduce appetite, increase energy expenditure, and improve insulin sensitivity without causing nausea that may be associated with GLP-1-based therapies, or loss of muscle mass.
“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,” stated associate professor Zach Gerhart-Hines, PhD, 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. Gerhart-Hines is senior author of the team’s published paper in Nature, titled “NK2R control of energy expenditure and feeding to treat metabolic diseases.” In their paper the scientists concluded, “These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programs to improve energy homeostasis and reverse cardiometabolic dysfunction across species.”
Millions of people around the world benefit from weight loss drugs based on the incretin hormone GLP-1. “The development of long-acting pharmacotherapies based on the incretin hormones—glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon (GCG)—has been transformative for the treatment of cardiometabolic diseases, such as obesity and type 2 diabetes,” the authors wrote. 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 due to common side effects, including nausea and vomiting. Studies also show that some incretin-based therapies are much less effective at lowering weight in people with both obesity and type 2 diabetes. “… for people living with both obesity and T2D, a group of more than 380 million people globally, the weight-lowering efficacy of GLP-1-derived pharmacotherapies is significantly reduced compared with those individuals with obesity but without T2D,” they continued.
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 generation of incretin-based therapies tip the scales toward a negative energy balance by lowering appetite and the total calories a person consumes. But scientists have also recognized the potential on the other side of the equation—increasing the calories the body burns. “The importance of targeting energy expenditure is particularly relevant given the steady decline in basal metabolic rate in the population over the past 40 years,” the team further pointed out. However, there are currently no clinically approved ways to safely increase energy expenditure, and few options are in development. “… although the current approved options and next generation of treatments (for example, amylin receptor agonists) have made major strides in producing lasting and more tolerable appetite suppression, a key gap is the lack of a means to increase energy expenditure.”
This was the starting point when scientists at the University of Copenhagen focused on testing the effect of activating the neurokinin 2 receptor (NK2R) in mice. The group identified the receptor through genetic screens that suggested NK2R played a role in maintaining energy balance and glucose control. “We set out to identify GPCR pathways that regulate energy homeostasis and could be leveraged to improve cardiometabolic health,” they explained.
Through their newly reported research the team were astonished to find that not only did activating the receptor safely increase calorie burning in mice, it also lowered appetite without any signs of nausea. “In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signaling,” the investigators stated. 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. “In our search, we uncovered a novel drug target whereby agonism of NK2R elicited increased peripheral energy expenditure and insulin sensitization as well as central control of appetite,” the team continued.
“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 nonhuman primates [with obesity], which represents a big step towards clinical translation,” said PhD student Frederike Sass from CBMR at the University of Copenhagen, and first author of the study. The authors added “We were fortunate to have the opportunity to test the early generation, prototypic NK2R agonist EB1001 in a cohort of older macaques. Every parameter that we were able to measure translated from our observations in rodents to the diabetic, macaques [with obesity], with the added benefit of reduced cholesterol and triglycerides.”
Recent advances in biopharmaceutical therapies for T2D and obesity have set what the authors called “incredibly high innovation bars.” However, they suggested, their work could result in the next generation of drug therapies that bring more efficacious and tolerable treatments for the nearly 400 million people globally who live with both type 2 diabetes and obesity. “… we believe that features of NK2R agonism such as energy expenditure with no signals of increased cardiovascular risk, lean mass sparing, lack of nausea and crucially, insulin sensitization, could complement the current drug repertoire, particularly in the context of individuals living with both obesity and T2D.”
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 Laboratories, Incipiam Pharma and Embark Biotech, which in 2023, was acquired by Novo Nordisk to develop next generation therapeutics for cardiometabolic disease.
