Millions of people around the world benefit from weight loss 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 due to common side effects, including nausea and vomiting. Studies also show that incretin-based therapies like Wegovy and Mounjaro are much less effective at lowering weight in people living with both obesity and type 2 diabetes - a group numbering more than 380 million people globally.
In a study published in Nature, scientists from the University of Copenhagen describe a powerful new 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. By addressing these needs, we believe our discovery will propel current approaches to make more tolerable, effective treatments accessible to millions more individuals," says Associate Professor Zach Gerhart-Hines from the NNF Foundation Center for Basic Metabolic Research (CBMR) at the University of Copenhagen.
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 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. 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 Neurokinin 2 Receptor (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. They were astonished by the results of the studies - 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," says 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.
Sass F, Ma T, Ekberg JH, Kirigiti M, Ureña MG, Dollet L, Brown JM, Basse AL, Yacawych WT, Burm HB, Andersen MK, Nielsen TS, Tomlinson AJ, Dmytiyeva O, Christensen DP, Bader L, Vo CT, Wang Y, Rausch DM, Kristensen CK, Gestal-Mato M, In Het Panhuis W, Sjøberg KA, Kernodle S, Petersen JE, Pavlovskyi A, Sandhu M, Moltke I, Jørgensen ME, Albrechtsen A, Grarup N, Babu MM, Rensen PCN, Kooijman S, Seeley RJ, Worthmann A, Heeren J, Pers TH, Hansen T, Gustafsson MBF, Tang-Christensen M, Kilpeläinen TO, Myers MG Jr, Kievit P, Schwartz TW, Hansen JB, Gerhart-Hines Z.
NK2R control of energy expenditure and feeding to treat metabolic diseases.
Nature. 2024 Nov 13. doi: 10.1038/s41586-024-08207-0