At risk. Changes in gut flora could help explain why obese mice are more likely to develop liver tumors (inset).

Eiji Hara/Japanese Foundation for Cancer Research

Three-in-one drug cuts body weight by a third

Gut surgery is often the only option for life-threatening obesity and diabetes, but what if doctors could cut the pounds without using a knife? Scientists have engineered an antiobesity drug that rivals the dramatic benefits seen with surgery, dropping excess body weight by a third. Though the work was done only in rodents, the drug is the first to influence three obesity-related hormones in the gut at once.

Bariatric surgery, including gastric bypass, typically involves limiting food intake by removing part of the stomach or intestines. Yet it does more than shrink the size of patient’s stomach or intestines. It also changes the release of multiple gut-related hormones, explains clinical endocrinologist Stephen O'Rahilly of the University of Cambridge in the United Kingdom, who wasn’t involved with the study. That’s important, because years of eating a diet high in fat and sugar can throw a person’s metabolism into disarray. Cells undergo genetic reprogramming that negatively impacts how they process sugar and store fat, locking in obesity. This pattern makes it harder and harder to lose weight, even if a person changes their diet and begins exercising.

Bariatric surgery interrupts that cycle by stimulating the production of several hormones that reduce blood sugar, burn fat, and curb appetite. (It may also change the composition of the gut’s microbes.) Three of these hormones are called glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP), and glucagon. Cells in your gut release GLP-1 and GIP after a meal to keep your body’s blood sugar levels in a normal range. GLP-1 also curbs appetite, signaling to your brain that you are full. In type 2 diabetes, the body stops responding to GLP-1 and GIP, which contributes to hyperglycemia, or too much blood sugar. Hyperglycemia causes the devastating hallmarks of diabetes, such as kidney injury, cardiovascular disease, and nerve damage.

Glucagon, in contrast, causes blood sugar levels to rise by telling the liver to convert fat into sugar. As hyperglycemia progresses in diabetes, the body shuts the hormone off in a presumed attempt to restore sugar balance, but that also stymies fat burning. In normal people and bariatric surgery patients, glucagon lowers fat and can trigger weight loss.

Existing medications can individually boost the levels of each of these hormones, but the drugs have a limited effect on obesity and diabetes. For instance, GLP-1 drugs only shave off an average of about 2.7 kilograms in human trials and also have unfortunate side effects like severe nausea and vomiting. These challenges have convinced many researchers that “the way forward with obesity drug therapy is hitting more than one gut hormone at once,” O'Rahilly says.

So that’s what endocrinologist Matthias Tschöp, research director of the Helmholtz Diabetes Center in Munich, Germany, and colleagues set out to do. They engineered a protein that takes structural pieces of GLP-1, GIP, and glucagon and merges them into a single molecule. To create the hybrid, the team started with an engineered protein that combined GLP-1 and glucagon, then spent years making small changes to add GIP components. Each time a tweak was made, the researchers would test the hybrid hormone in cells or mice to see if it still stimulated each hormone pathway. By the end, they had a drug packed with the power to turn on glucagon, GLP-1 and GIP signals, but not other hormone systems—an unprecedented feat for obesity drug design.

When given to obese and diabetic rodents, the drug triggered metabolic changes—glucose lowering, fat burning, and weight loss—to the same degree that bariatric surgery had in previous studies. The compound caused the rodents’ body weight to drop by a third, on average, over 3 weeks and cut their blood glucose in half. It also reduced fat mass by a third, while keeping healthy lean mass intact, Tschöp and his colleagues report online today in Nature Medicine.

“Think of this as an injectable elixir that could reverse obesity and type 2 diabetes by cheating a body into believing that it just received a gastric bypass,”  Tschöp says. That means a commercial drug based on this research could potentially confer the benefits of bariatric surgery without the risks of a physical operation.

The project required some remarkably clever chemistry and is one of the more thorough evaluations of a drug for obesity and diabetes, O'Rahilly says, though he points out that true test will come in humans. ”In the end, you don't throw a party until you have a drug that works in people.”