Insulin resistance drug instead tackles obesity

Australian researchers have developed a drug that has been described as a major step forward in the battle against our escalating rates of obesity and its associated diseases — and with two in three adults in Australia currently classified as being overweight or obese, it could be just what the doctor ordered.

Published in the journal Nature Communications, the project was a collaboration between the Centenary Institute and UNSW Sydney, who set out to create a drug that targeted enzymes within the ceramide synthase family. This family produces lipid molecules believed to promote insulin resistance in skeletal muscle, as well as liver and fat tissue — a key contributor of metabolic diseases, such as type 2 diabetes.

Ceramide lipids are involved in regulating metabolic physiology; however, the role of different ceramides is not fully understood. Inhibition of certain ceramide synthases is believed to produce benefits for metabolic health, whereas inhibition of others is likely to be detrimental.

Until now, inhibitors with sufficient potency, selectivity and suitable properties for use in a living organism have not yet been developed. That has now changed with the researchers’ synthesis of a small molecule, known as P053, which inhibits the enzyme ceramide synthase 1 (CerS1) — although the subsequent effect of the drug was not as expected.

Although the drug was very effective at reducing the lipids of interest in skeletal muscle, it did not prevent mice (which had been fed a high-fat diet to induce metabolic disease) from developing insulin resistance. Instead, it prevented the mice from depositing and storing fat by increasing their ability to burn fat in skeletal muscle.

“We anticipated that targeting this enzyme would have insulin-sensitising, rather than anti-obesity, effects,” said UNSW Associate Professor Nigel Turner. “However, since obesity is a strong risk factor for many different diseases, including cardiovascular disease and cancer, any new therapy in this space could have widespread benefits.”

By developing a small molecule to specifically inhibit CerS1, the authors show that this enzyme has a significant role in the endogenous regulation of muscle fatty acid oxidation and whole body fat storage. The results also open up a potential new therapeutic avenue for the treatment of obesity, although further studies are required to determine if these findings translate to humans.

“From here, I would like to develop drugs which target both the ceramide synthase 1 and 6 enzymes together and see whether it produces a much stronger anti-obesity and insulin-sensitising response,” said the Centenary Institute’s Associate Professor Anthony Don. “Although these drugs need more work before they are suitable for use in the clinic, our work so far has been a very important step in that direction.”

Image credit: ©stock.adobe.com/au/Andrey Popov