Obesity in mice helped by chemotherapy drugs, Mayo Clinic research suggests

Investigators at Mayo Clinic in Arizona have observed that two common cancer-fighting drugs sparked significant weight loss in mice with obesity even though the mice continued their excessive consumption of a high-fat diet. The results, part of a Mayo Clinic study, were reported in the Jan. 17, 2017, edition of Oncotarget.

“When the morbidly obese mice were treated with certain cancer-fighting drugs, the drugs not only targeted their cancers but also tended to spontaneously resolve their obesity, even with undiminished gorging on a high-fat diet,” says Peter Cohen, M.D. (HEMO ’08), Division of Hematology/Oncology, who led the study with postdoctoral fellow Cheryl Meyers, Ph.D. (BIOC ’15), and Sandra Gendler, Ph.D. (BIOC ’93), Department of Biochemistry and Molecular Biology.

The two chemotherapy agents – methotrexate and cyclophosamide – could be dosed to completely reverse obesity without detectable toxicity, even in mice with cancer. More research is necessary to see if the same outcome can be achieved in morbidly obese patients.

Mice obesity improved with ease

“The ease with which the weight loss was achieved in mice is in stark contrast to the Herculean difficulties morbidly obese patients experience trying to preserve weight loss through dietary restraint,” says Dr. Gendler.

The weight reduction observed in the obese mice were not attributable to trivial explanations, such as a decrease in dietary intake, increased energy expenditure or malabsorption. Instead, investigators identified multiple effects of the drugs that worked together to expedite loss of excessive weight in mice. Much like chemotherapy’s well-known ability to decrease red and white blood cell precursors transiently, methotrexate or cyclophosphamide depleted fat cell precursors, leading to much decreased fat storage. “This meant that excessive dietary calories had to go somewhere else in the body instead, such as to the liver,” says Dr. Cohen.

“Surprisingly, the liver maintained a robust level of metabolic activity during methotrexate or cyclophosphamide treatment but was nearly shut down in regard to fat production and fat storage,” says Dr. Myers.

“Based on our composite data, it appears that methotrexate or cyclophosphamide can induce the livers of obese mice to burn off rather than accumulate excessive dietary fat,” says Dr. Gendler. “This results in desirable weight reduction instead of increased obesity, even with continued caloric binging.”

The study sets the stage for further research, exploring how these metabolic mechanisms could reduce the need for severe dietary constraints in morbidly obese individuals.