Imagine the benefits of gastric bypass surgery without going under the knife—a new class of compounds may be able to do just that. These potential treatments significantly reduce body weight and blood glucose levels in laboratory animals. The injectable compounds also prevent nausea and vomiting that are common side effects of current weight loss and diabetes medications. Scientists now report that a new treatment not only reduces food intake but also increases calorie burn.
The researchers presented their results at the spring meeting of the American Chemical Society (ACS). ACS Spring 2023 is a hybrid meeting held virtually and in person March 26-30, and features more than 10,000 presentations on a wide range of science topics. “Obesity and diabetes were epidemics before the COVID-19 pandemic,” says Robert Doyle, PhD, one of the project’s two principal investigators, along with Christian Roth, MD, “They are huge problems, and they are. Only predicted to get worse.”
Gastric bypass and related procedures, collectively known as bariatric surgery, offer a solution, often permanent weight loss and even remission of diabetes. But these operations carry risks, are not suitable for everyone and are inaccessible to many of the millions of people around the world who are obese or diabetic. As an alternative, Doyle says, they can fix their metabolic problems with drugs that replicate the long-term benefits of surgery.
Those benefits are linked to post-bypass-surgery changes in intestinal secretion levels of hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY)—which normalize fullness, appetite reduction, and weight gain. blood sugar Current drugs that aim to replicate this effect primarily activate cellular receptors for GLP-1 in the pancreas and brain. That approach has shown great success in weight loss and treating type 2 diabetes, drawing numerous social media posts from celebrities in recent months. But many people can’t tolerate the side effects of the drugs, Doyle says. “Within a year, 80 to 90% of people who start these drugs are no longer taking them.” Doyle is at Syracuse University and SUNY Upstate Medical University, and Roth is at the Seattle Children’s Research Institute.
To address that shortcoming, various researchers have designed other treatments that interact with more than one type of gut hormone receptor. For example, Doyle’s group created a peptide that activates two receptors for PYY, as well as a receptor for GLP-1. Dubbed GEP44, the compound caused obese mice to eat 80% less than they normally would. At the end of a 16-day study, they lost an average of 12% of their weight. This was three times more than the amount lost by mice treated with liraglutide, an injected drug that activates only the GLP-1 receptor and which is approved by the US Food and Drug Administration for the treatment of obesity.
In contrast to liraglutide, tests of GEP44 in mice and shrews (a mammal that, unlike rats, are capable of vomiting) showed no signs of nausea or vomiting, possibly because activating more receptors can abrogate the intracellular signaling pathways that drive those symptoms, Doyle says. As a result, his team now shows that weight loss caused by GEP44 can be traced not only to a reduction in food intake, but also to higher energy expenditure, which can lead to an increase in speed, heart rate or body temperature. .
GEP44 has a half-life of only one hour in the body, but Doyle’s group recently designed a peptide with a much longer half-life. This means it can be injected only once or twice a week instead of several times a day. Researchers are now reporting that mice treated with this next-generation compound keep their new, slimmer bodies long after treatment ends, which is often not the case with currently approved drugs, Doyle says.
But weight loss isn’t the only benefit of peptide treatments. They also lower blood sugar by drawing glucose into muscle tissue, where it can be used as fuel, and by converting some cells in the pancreas into insulin-producing cells, helping to replace those damaged by diabetes. And there’s yet another benefit: Doyle and Heath Schmidt, Ph.D., of the University of Pennsylvania, recently reported that GEP44 reduces cravings for opioids like fentanyl in mice. If it works in humans, Doyle says, it could help addicts avoid or relapse to illegal drugs.
The researchers have filed for patents on their compounds, and they plan to test their peptides in primates. They will also study how the treatment changes gene expression and rewires the brain, and what that might mean for these compounds, as well as other types of drugs.
“For a long time, we didn’t think you could lose weight from nausea and vomiting, because they’re linked to the exact same part of the brain,” says Doyle. But researchers have now linked those two pathways — and have implications for chemotherapy, which causes similar side effects. What if we could maintain the benefits of chemotherapy drugs and tell the part of the brain that causes nausea and vomiting? Then we can dose patients at a higher level, so they have a better prognosis and a better quality of life while they’re also on chemotherapy,” he says.
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