New Weight Loss Drug Boosts Energy and Reduces Appetite Without Side Effects

Researchers at the University of Copenhagen have identified a new drug target for weight loss that curbs appetite, boosts energy use, and enhances insulin sensitivity without causing nausea or muscle loss. This discovery may pave the way for effective treatments for obesity and type 2 diabetes.

Millions worldwide benefit from weight loss drugs derived from the incretin hormone GLP-1. These medications not only aid in weight management but also enhance kidney function, lower the risk of fatal cardiac events, and show potential in protecting against neurodegeneration.

However, many individuals discontinue these medications due to common side effects such as nausea and vomiting. Additionally, research indicates that incretin-based therapies like Wegovy and Mounjaro are significantly less effective in promoting weight loss among people with both obesity and type 2 diabetes—a population exceeding 380 million worldwide.

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.

NK2R activation lowers 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 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. 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 the 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.

Reference: “NK2R control of energy expenditure and feeding to treat metabolic diseases” by Frederike Sass, Tao Ma, Jeppe H. Ekberg, Melissa Kirigiti, Mario G. Ureña, Lucile Dollet, Jenny M. Brown, Astrid L. Basse, Warren T. Yacawych, Hayley B. Burm, Mette K. Andersen, Thomas S. Nielsen, Abigail J. Tomlinson, Oksana Dmytiyeva, Dan P. Christensen, Lindsay Bader, Camilla T. Vo, Yaxu Wang, Dylan M. Rausch, Cecilie K. Kristensen, María Gestal-Mato, Wietse In het Panhuis, Kim A. Sjøberg, Stace Kernodle, Jacob E. Petersen, Artem Pavlovskyi, Manbir Sandhu, Ida Moltke, Marit E. Jørgensen, Anders Albrechtsen, Niels Grarup, M. Madan Babu, Patrick C. N. Rensen, Sander Kooijman, Randy J. Seeley, Anna Worthmann, Joerg Heeren, Tune H. Pers, Torben Hansen, Magnus B. F. Gustafsson, Mads Tang-Christensen, Tuomas O. Kilpeläinen, Martin G. Myers Jr, Paul Kievit, Thue W. Schwartz, Jakob B. Hansen and Zachary Gerhart-Hines, 13 November 2024, Nature.
DOI: 10.1038/s41586-024-08207-0

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