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New compounds offer dramatic weight loss without side effects

A new class of injectable compounds mimic the benefits of gastric bypass surgery – inducing weight loss and lowering blood glucose - whilst avoiding the unpleasant side effects of nausea and vomiting that are common with current weight-loss and diabetes drugs. The researchers have reported that the new treatment not only reduces eating but also boosts calorie burn. The researchers presented the results at the spring meeting of the American Chemical Society (ACS).

“Obesity and diabetes were the pandemic before the COVID-19 pandemic,” says Dr Robert Doyle, one of the two principal investigators on the project, along with Dr Christian Roth, “They are a massive problem and they are projected to only get worse. For a long time, we didn't think you could separate weight reduction from nausea and vomiting, because they’re linked to the exact same part of the brain. But the researchers have now uncoupled those two pathways, tackling their metabolic problems with a drug that replicates the long-term benefits of surgery.”


Current drugs that aim to replicate post-bypass-surgery change in the gut’s secretion levels of certain hormones — including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) — that signal fullness, curb appetite and normalise blood sugar, this effect primarily activate cellular receptors for GLP-1 in the pancreas and brain.


“That approach has shown great success in reducing weight and treating type 2 diabetes, but many people can’t tolerate the drugs’ side effects,” added Doyle. “Within a year, 80 to 90% of people who start on these drugs are no longer taking them.” Doyle is at Syracuse University and SUNY Upstate Medical University, and Roth is at Seattle Children’s Research Institute.

To address that drawback, 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 the receptor for GLP-1. Dubbed GEP44, this compound caused obese rats to eat up to 80% less than they would typically eat. By the end of one 16-day study, they lost an average of 12% of their weight. That was more than three times the amount lost by rats treated with liraglutide, an injected drug that activates only the GLP-1 receptor and that is approved by the FDA for treating obesity. In contrast to liraglutide, tests with GEP44 in rats and shrews (a mammal that, unlike rats, is capable of vomiting) revealed no sign of nausea or vomiting, possibly because activating multiple receptors may cancel out the intracellular signalling pathway that drives those symptoms, Doyle explained.


In its latest results, his team is now reporting that the weight loss caused by GEP44 can be traced not only to decreased eating, but also to higher energy expenditure, which can take the form of increased movement, heart rate or body temperature.


GEP44 has a half-life in the body of only about an hour, but Doyle’s group has just designed a peptide with a much longer half-life. That means it could be injected only once or twice a week instead of multiple times a day. The researchers are now reporting that rats treated with this next-generation compound keep their new, slimmer physique even after treatment ends, which often isn’t the case with currently approved drugs.


But weight loss isn’t the only benefit of the peptide treatments. They also reduce blood sugar by pulling glucose into muscle tissue, where it can be used as fuel, and by converting certain cells in the pancreas into insulin-producing cells, helping replace those that are damaged by diabetes. And there’s yet another benefit: Doyle and Dr Heath Schmidt of the University of Pennsylvania, recently reported that GEP44 reduces the craving for opioids such as fentanyl in rats. If that also works in humans, Doyle added, it could help addicts quit the illicit drugs or fend off a relapse.


The researchers have filed for patents on their compounds, and they plan to test their peptides in primates. They will also study how the treatments change gene expression and rewire the brain, and what that could mean for these compounds, as well as other types of medication.


The researchers acknowledge funding from the Congressionally Directed Medical Research Programs of the US Department of Defense, which is interested in the topic because many veterans have weight-related type 2 diabetes.

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