Lipids, the chemical family that includes fats and related molecules, get blamed for clogged arteries and heart attacks. But thanks to careful detective work tracking the effects of a particular protein, researchers have discovered a class of lipids that prevent or reverse some of the harmful metabolic changes of diabetes and similar disorders in mice. These molecules might be therapeutic themselves, or they could lead researchers to new drugs.
Although many lipids are beneficial, some of them deserve their bad reputation, especially certain fatty acids, which sport long chains of carbon and hydrogen atoms. Trans fatty acids in processed foods can jack up our levels of unhealthy cholesterol, for instance, and studies have linked diabetes and obesity to increased amounts of fatty acids in the blood.
The new study puts fatty acids in a better light. Its origins date back to the 1990s. Researchers noticed that fat cells from people who were obese or had type 2 diabetes often carried too little Glut4, a protein that helps cells absorb sugar. “It’s very important for blood sugar control,” says molecular endocrinologist Barbara Kahn of Harvard Medical School in Boston. To study the effects of this protein, she and her colleagues genetically altered mice so that their fat cells produced extra Glut4 and gobbled up sugar.
These mice have puzzled scientists ever since. Although they are obese, they have the blood glucose and insulin levels of sleek and healthy rodents. The bonus Glut4, it appears, triggered production of extra lipids in their fat cells. Kahn and her colleagues hypothesized that some of these lipids were beneficial and explained the rodents’ healthy metabolism.
To hunt for these mystery molecules, Kahn’s group teamed up with lipid biologist Alan Saghatelian of the Salk Institute for Biological Studies in San Diego, California, and some of his colleagues. Using a technique called mass spectrometry that can weigh and identify molecules in a sample, the researchers pinpointed four lipids that were more abundant in the Glut4-overproducing mice and deciphered their molecular formulas.
But these molecules were nowhere to be found in standard lipid catalogs. “We were dealing with something new,” Saghatelian says. In all, the researchers uncovered 16 closely related fatty acids that they dubbed FAHFAs, or fatty acid-hydroxy fatty acids.
Experiments to tease out the molecules’ metabolic roles suggested they are salutary. In one experiment, for example, the researchers force-fed FAHFAs to normal mice that had been eating a high-fat diet and were insulin-resistant, meaning they didn’t respond normally to the hormone. Blood sugar plunged in the animals, and their glucose tolerance, or ability to absorb the molecule, rose. Providing FAHFAs to the animals “treats their diabetes,” Saghatelian says.
FAHFAs are not limited to mice. Kahn and Saghatelian’s team tested blood and fat from patients who are insulin-resistant—and thus at greater risk of developing diabetes—and from patients who are still insulin-sensitive. Blood levels of one FAHFA variety were 40% lower in the insulin-resistant group, the team reports this week in Cell.
Researchers rarely find new families of lipids, says cell biologist Alan Saltiel of the University of Michigan, Ann Arbor, who was not involved in the work. The lipids appear to stimulate a biochemical pathway that researchers are already probing as a target for diabetes drugs, he says. If further studies confirm this mechanism, FAHFAs might suggest new ways that researchers could modify the pathway.
One intriguing question is whether restoring FAHFA levels could help prevent or treat diabetes. The researchers discovered FAHFAs in a variety of foods, including apples, egg yolk, beef, and chicken. However, Kahn says it's premature to recommend that people alter their diets to try to consume more of the molecules. Even if chowing down on the fatty acids isn’t helpful, their discovery could still spark new treatments. Investigating the enzymes that produce and destroy FAHFAs in the body might help researchers develop drugs to adjust quantities of the fatty acids.