Scientists once had high hopes that inhibiting a hormone named ghrelin would be the key to preventing obesity. Ghrelin didn’t turn out to be a weight loss panacea. But now, the discovery of the first molecule naturally made by the body that blocks ghrelin’s effects may open up new avenues for treating other conditions, including diabetes and anorexia. The finding may also explain some of the benefits of bariatric surgery, which shrinks or reroutes the stomach to control weight.
“It’s a very impressive piece of research,” says bariatric physician Carel le Roux of University College Dublin, who wasn’t connected to the study. “I think it will have significant clinical impact.”
When researchers discovered ghrelin about 20 years ago, they dubbed it the “hunger hormone” because early results suggested it ramped up our appetite. But studies soon found that thwarting the molecule didn’t curtail food consumption or promote weight loss in mice. Still, the hormone induces a variety of other positive changes in our metabolism. For example, ghrelin may bolster muscle strength, spurring scientists to test whether drugs that mimic the hormone can counteract the muscle deterioration and weakness often suffered by cancer patients.
The new study didn’t start as a hunt for ghrelin-blocking compounds. Instead, a team headed by researchers at NGM Biopharmaceuticals in South San Francisco, California, was investigating how bariatric surgery overhauls metabolism. The scientists operated on obese mice, performing a type of bariatric surgery called vertical sleeve gastrectomy that involves removing most of the stomach. They then examined which genes became more or less active after the procedure. As they report online today in Cell Metabolism, the rodents’ downsized stomachs produced 52 times more of a protein named LEAP2 than normal.
Typically, LEAP2 comes from the liver and small intestine, not the stomach, but what it does isn’t clear. To investigate its function, the researchers tested whether the hormone stimulates or blocks an assortment of human receptor proteins, which allow our cells to respond to different molecular signals. They discovered that LEAP2 inhibits the receptor for ghrelin by fastening to it and possibly preventing ghrelin from latching on.
Next, the researchers wanted to determine whether LEAP2 also foils ghrelin in the body. One of ghrelin’s important roles appears to be preventing blood sugar from plummeting when food is scarce. Ghrelin exerts this protective effect by spurring release of growth hormone, which in turn triggers the synthesis of glucose. Injecting food-deprived mice with ghrelin sparks a surge in growth hormone, but the scientists found that giving the mice a shot of LEAP2 as well prevented that increase.
The team further delved into LEAP2’s role by genetically modifying mice to produce three times the normal amount of the protein. After a week on an extremely low calorie diet, the altered mice showed dramatically reduced blood glucose levels and became extremely weak. “They don’t have the strength to jump on the food and eat it,” says co-author Xuecai Ge, now a cell biologist at the University of California, Merced.
The study shows that LEAP2 is “a new, important part of the ghrelin system that is essential for our survival,” says endocrinologist Jeffrey Zigman of the University of Texas Southwestern Medical Center in Dallas. “Time will tell whether it can be targeted” to treat conditions such as obesity, anorexia, and diabetes, he says.
Le Roux points out one way in which LEAP2 could help fight obesity. People who lose weight often gain it back because their appetite revs up, possibly because of a corresponding rise in ghrelin levels. Using LEAP2 or a similar molecule, perhaps “we can prevent that almost inevitable hunger that follows weight loss,” he says.
But endocrinologist Jenny Tong of Duke University School of Medicine in Durham, North Carolina, says that researchers don’t know enough yet about the role of ghrelin in conditions like obesity and diabetes to begin discussing using LEAP2 for treatments. Nevertheless, she says, the study provides a new way to investigate ghrelin’s functions. “Now, we have a tool to manipulate the ghrelin system,” she says.