Blocking Arginine Metabolism Leads to Improved Metabolic Health and Weight Loss – ScienceDaily

According to a new study in mice by researchers at Washington University School of Medicine in St. Louis, a cancer drug in development that deprives tumors of their energy supply also shows evidence of an improvement in overall body metabolism, leading to improved weight control.

The results are published in the journal Cell Reports Medicine.

In a group of mice genetically predisposed to obesity and in a separate group of mice that became obese as a result of a high-fat, high-sugar diet, treatment with the drug ADI-PEG 20 increased insulin sensitivity, improved cholesterol levels, and reduced blood cholesterol Fat buildup in the liver and lowered inflammation. In the mice, which were genetically predisposed to obesity from birth, treatment with the drug protected them from their typical weight gain. And in the mice that became obese on a high-fat, high-sugar diet, treatment with the drug resulted in weight loss.

The drug is currently being studied for possible use to treat a range of cancers, including sarcoma, breast and pancreatic cancer. The drug breaks down the amino acid arginine in the blood, depriving cancer cells of an important source of energy. Researchers became interested in studying the drug after finding that genes responsible for breaking down arginine are tremendously dialed up when the body is in a fasted state. They wondered if the drug could mimic this effect of fasting.

In fact, the researchers found that the drug prompts cells to undergo a process called autophagy, or self-eating, a cellular-level house-cleaning process. Cells undergoing autophagy burn their own cellular waste products for fuel. During fasting, when no new fuel comes from the outside, the cells switch to autophagy and turn inward for their fuel supply.

“Giving this drug appears to mimic some of the metabolic and therapeutic effects of fasting,” said senior author Brian DeBosch, MD, PhD, associate professor of pediatrics. “I was surprised how big the effect was. Of the mice that tended to gain weight, the group that received the drug ended up weighing about 25% less than the mice that didn’t receive the drug. And in the mice on the high-fat, high-sugar diet, we saw similar weight loss from the drug. We also don’t think that the vast majority of the drug’s metabolic benefits are due to changes in body weight. In fact, in several outcome measurements, the metabolic changes preceded significant weight changes.”

The drug has been tested in clinical trials examining its safety and effectiveness in treating various types of tumors, including breast, prostate, pancreas and liver cancer. In general, metabolic therapies tend to have fewer side effects and are safer than chemotherapy, radiation, and even newer immunotherapies used to treat cancer.

DeBosch, a pediatric gastroenterologist who treats patients at St. Louis Children’s Hospital, said the research team would like to conduct a clinical trial of the drug to see if it induces similar metabolic benefits and weight loss in overweight or obese people. One question that remains is whether the drug is safe to take long-term. It’s not a small molecule like a statin that can be taken for decades. The drug is a protein, so there’s a chance patients could develop an immune response to it over time. However, DeBosch still sees a potential role for such treatment over weeks to months.

“Many obese patients considering bariatric surgery need to lose some weight first to make the procedure safer,” DeBosch said. “For such patients, it can be difficult to lose up to 10% of their body weight before surgery. This type of therapy could potentially serve as a bridge to help patients lose weight before bariatric surgery and reduce the risk of complications during and after the procedure.”

This work was supported by National Institutes of Health (NIH) grant numbers 1R01DK126622-01A1, 1R01HL147968-01A1, 1R21AT010520-01, UL1TR002345, and R56 DK115764; a Pilot Research Award from the American Association for the Study of Liver Disease; an AGA-Gilead Sciences Research Scholar Award for Liver Disease; the AGA-Allergan Foundation Pilot Research Award for Nonalcoholic Fatty Liver Disease; the Washington University Digestive Disease Research Core Center, grant number P30DK52574; the Washington University Diabetes Research Center, grant number P30DK020579; the Nutrition & Obesity Research Center, grant number P30DK056341; the Association for Aging Research Junior Faculty Award; the Robert Wood Johnson Foundation; the Washington University Center for Autophagy Therapeutics Research; the Longer Life Foundation; and a Washington University School of Medicine Pediatric Gastroenterology Research Training Grant research grant number T32DK077653.

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