May 19, 2020

Repurposed drug combats obesity in mice

At a Glance

  • Obese mice lost weight and showed improved metabolic function when treated with a drug that’s normally prescribed for alcohol use disorder.
  • Further testing will be needed to determine whether the drug could be effective for treating obesity in people.
Disulfiram molecule Mice made obese from a high fat diet were switched to a diet dosed with disulfiram (Antabuse), shown here, which helped them lose weight and improve their metabolic health. serge001 / iStock / Getty Images Plus

Obesity is a top public health concern. Being obese increases the risk for a variety of health problems, including heart disease, type 2 diabetes, and certain types of cancer. Excess body weight can cause harmful changes in metabolism—the process by which we turn the energy we eat into fuel for the body’s cells. These metabolic problems can damage many organs, including the liver and pancreas.

Eating a diet high in fat and simple sugars can lead to excess weight as well as chronic, low-grade inflammation in the body. An improved diet and increased physical activity can help reduce body fat, but maintaining a healthy weight can be challenging. Researchers have thus been working to develop new treatments for obesity.

A research team led by Drs. Michel Bernier and Rafael de Cabo of NIH’s National Institute on Aging (NIA) investigated the use of the medication disulfiram for treating obesity in mice. This drug has been prescribed for alcohol use disorder for over 50 years. Sold under the brand name Antabuse, it is known to have anti-inflammatory properties. The researchers became interested in disulfiram after reading about the benefits this class of drug has shown in treating type 2 diabetes in rats.

The researchers fed middle-aged lab mice a high-fat diet for 12 weeks. The mice became overweight and started showing signs of metabolic problems similar to pre-diabetes. These included insulin resistance and elevated fasting blood sugar levels.

The mice were then assigned to one of four diets for 12 weeks: a standard diet alone, a high-fat diet alone, a high-fat diet with a low amount of disulfiram, or a high-fat diet with a higher amount of disulfiram. Results were published in Cell Metabolism on May 14, 2020.

As expected, the mice that stayed on the high-fat diet alone continued to gain weight and show metabolic problems. Mice switched to a standard diet gradually saw their body weight, fat composition, and blood sugar levels return to normal.

The mice receiving disulfiram with their still-fatty food showed a dramatic decrease in their body weight and related metabolic damage. Those on the higher disulfiram dose lost as much as 40% of their body weight in just four weeks. Their leaner weight was similar to that of mice switched to a standard diet. Disulfiram treatment also appeared to protect the pancreas and liver from damage.

None of the mice were subjected to exercise, nor did they show changes in behavior that might have affected body weight. This suggests that the benefits were solely from the disulfiram treatment.    

“When we first went down this path, we did not know what to expect, but once we started to see data showing dramatic weight loss and leaner body mass in the mice, we turned to each other and couldn’t quite believe our eyes,” Bernier says.

It’s unclear whether disulfiram would benefit people in a similar way. Past clinical studies of the drug haven’t focused on weight loss or other metabolic measures. Experts caution against off-label use of the medication before its effects on weight management in people are understood.

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References: Disulfiram Treatment Normalizes Body Weight in Obese Mice. Bernier M, Mitchell SJ, Wahl D, Diaz A, Singh A, Seo W, Wang M, Ali A, Kaiser T, Price NL, Aon MA, Kim EY, Petr MA, Cai H, Warren A, Di Germanio C, Di Francesco A, Fishbein K, Guiterrez V, Harney D, Koay YC, Mach J, Enamorado IN, Pulpitel T, Wang Y, Zhang J, Zhang L, Spencer RG, Becker KG, Egan JM, Lakatta EG, O'Sullivan J, Larance M, LeCouteur DG, Cogger VC, Gao B, Fernandez-Hernando C, Cuervo AM, de Cabo R. Cell Metab. 2020 May 7. pii: S1550-4131(20)30236-9. doi: 10.1016/j.cmet.2020.04.019. PMID: 32413333.

Funding: NIH’s National Institute on Aging (NIA) and National Institute of Alcohol Abuse and Alcoholism (NIAAA); Yale University; Albert Einstein College of Medicine; Korea Research Institute of Bioscience and Biotechnology; University of Sydney, Australia.