New drug candidate reverses obesity in mice

Mitochondria are essential for human health, as they process the nutrients in the food we eat and harvest the energy needed for various processes in the cell. They are central regulators of metabolism, which is very dynamic and can be rerouted and reprogrammed according to different needs or in response to disease.

Increased fat metabolism

Professor Nils-Göran Larsson’s research group at Karolinska Institutet has recently developed highly specific drug candidates that block mitochondrial function, and thus cellular energy production, to treat cancer. Now the researchers have shown that these drugs also have a beneficial effect on metabolism in mice.

“Four weeks of treatment led to an unexpected increase in fat metabolism, resulting in a drastic weight loss, a reduction in fat accumulation in the liver and restored glucose tolerance,” says postdoctoral researcher Taolin Yuan at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.

The treatment was given orally to male obese mice who had been fed a high-fat diet. The surprising effect suggests that blocking the cells’ energy production can reverse obesity and diabetes.

Collaboration with a biotech company

“It’s exciting that we have identified a new potential strategy for treating common diseases like obesity and type 2 diabetes,” says Professor Nils-Göran Larsson. “We now aim to further investigate the mechanisms that can explain the drugs’ effect. We have also initiated a collaboration with a biotech company to see if this can be further developed into a treatment for humans. Still, it will be many years before we know if it works,” he concludes.

The study was financed by the Novo Nordisk Foundation, the Swedish Diabetes Foundation, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, ALF funding, the Swedish Cancer Society and the Swedish Brain Foundation. Nils-Göran Larsson is a scientific founder and holds stock in Pretzel Therapeutics Inc. Three of the coauthors are employees of Lead Discovery Center and are listed as co-inventors on a patent application concerning mitochondrial RNA polymerase inhibitors for the treatment of cancer. The remaining authors declare no competing interests.Publication: “Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity”, Shan Jiang, Taolin Yuan, Florian A. Rosenberger, Arnaud Mourier, Nathalia R. V. Dragano, Laura S. Kremer, Diana Rubalcava-Gracia, Fynn M. Hansen, Melissa Borg, Mara Mennuni, Roberta Filograna, David Alsina, Jelena Misic, Camilla Koolmeister, Polyxeni Papadea, Martin Hrabe de Angelis, Lipeng Ren, Olov Andersson, Anke Unger, Tim Bergbrede, Raffaella Di Lucrezia, Rolf Wibom, Juleen R. Zierath, Anna Krook, Patrick Giavalisco, Matthias Mann & Nils-Göran Larsson, Nature Metabolism, online 30 April 2024, doi: 10.1038/s42255-024-01038-3.