Weight loss drug suppresses appetite, burns energy and skips side effects

Scientists at the University of Copenhagen have identified a target for weight loss drugs, the neurokinin 2 receptor (NK2R), which they say could lead to a new therapeutic strategy for millions of people with obesity and type 2 diabetes (T2D). do not respond well to current treatments. In addition, the team developed an NK2R agonist candidate that, when tested in various animal models, reduces appetite, increases energy expenditure, and improves insulin sensitivity without causing nausea that can be associated with GLP-1-based therapies or loss of insulin muscle mass.

“While GLP-1-based therapies have revolutionized patient care for obesity and type 2 diabetes, safe use of energy expenditure and control of appetite without nausea remain two holy grails in the field,” explained Associate Professor Zach Gerhart-Hines, PhD, from the NNF Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen. “We believe that by addressing these needs, our discovery will advance current approaches to make more tolerable and effective treatments available to millions more people.” Gerhart-Hines is senior author of the team's published work in Natureentitled “NK2R control of energy expenditure and nutrition for the treatment of metabolic diseases”. In their paper, the scientists concluded: “These results identify a single receptor target that utilizes both energy-consuming and appetite-suppressing programs to improve energy homeostasis and reverse cardiometabolic dysfunction across species.”

Millions of people around the world benefit from weight loss medications 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 fundamentally changed 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 medication due to common side effects such as nausea and vomiting. Studies also show that some incretin-based therapies are significantly less effective at reducing weight in people with obesity and type 2 diabetes. “…in people suffering from both obesity and T2D, a group of more than 380 million people worldwide, the weight-lowering efficacy of GLP-1-derived pharmacotherapies is significantly lower compared to 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 leads to a positive energy balance, leading to weight gain, while eating less and burning more leads to a negative energy balance, leading to weight loss.

The current generation of incretin-based therapies creates a negative energy balance by reducing appetite and the total amount of calories a person consumes. But scientists have also recognized the potential on the other side of the equation – increasing the number of calories the body burns. “In view of the constant decline in the population's basal metabolic rate over the last 40 years, it is particularly important to specifically control energy consumption,” the team further emphasized. However, there are currently no clinically approved methods to safely increase energy expenditure, and few options are in development. “…although currently approved next-generation options and treatments (e.g., amylin receptor agonists) have made great strides in achieving durable and more tolerable appetite suppression, a critical gap remains 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 studies, which suggested that NK2R plays a role in maintaining energy balance and glucose control. “We wanted to identify GPCR signaling pathways that regulate energy homeostasis and could be used to improve cardiometabolic health,” they explained.

The team was amazed to find in their newly published study that activating the receptor not only safely increased calorie burning in mice, but also reduced appetite without causing any signs of nausea. “In mice, these agonists trigger weight loss by inducing energy expenditure and non-aversive appetite suppression that bypasses canonical leptin signaling,” the researchers explained. Further studies in non-human primates with type 2 diabetes and obesity showed that NK2R activation reduced body weight and reversed their diabetes by increasing insulin sensitivity and lowering blood sugar, triglycerides and cholesterol. “In our search, we discovered a novel drug target in which agonism of NK2R produces 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. For this reason, we were excited that the benefits of NK2R agonism could be translated to diabetics and non-human primates [with obesity]which represents a big step towards clinical translation,” said doctoral 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 prototypical NK2R agonist EB1001 in a cohort of older macaques.” Every parameter we were able to measure was adapted from our observations in diabetic rodents , macaques, transmitted [with obesity]with the added benefit of reducing cholesterol and triglycerides.”

Recent advances in biopharmaceutical therapies for type 2 diabetes and obesity have set what the authors call “incredibly high standards of innovation.” But they suggested that their work could lead to the next generation of drug therapies, enabling more effective and tolerable treatments for the nearly 400 million people worldwide living with both type 2 diabetes and obesity. “…we believe that features of NK2R agonism such as energy expenditure without evidence of increased cardiovascular risk, muscle mass sparing, lack of nausea and, most importantly, insulin sensitization could complement the current drug repertoire, particularly in the context of individuals living with both obesity and T2D.”

The University of Copenhagen owns the patent rights for targeting NK2R. To date, the Gerhart Hines Laboratory's research has led to the creation of three biotech companies: Embark Laboratories, Incipiam Pharma and Embark Biotech, which was acquired by Novo Nordisk in 2023, to develop next-generation therapeutics for cardiometabolic diseases.