Einstein researchers have found a molecular explanation for the hunger pangs caused by lack of food. Their discovery could lead to an entirely new way to treat obesity and the type 2 diabetes that often results from it.
Scientists have long known that starvation activates a process called autophagy, in which cells cannibalize some of their own components to survive. Autophagy also provides an "important cellular recycling mechanism" that allows cells to digest organelles and damaged proteins they no longer need, says Rajat Singh, M.D., M.B.B.S. (right), an assistant professor of medicine (endocrinology) and of molecular pharmacology.
But autophagy does more than recycle cellular trash for energy. As a postdoctoral fellow working with Einstein’s Mark J. Czaja, M.D., and Ana Maria Cuervo, M.D., Ph.D., Dr. Singh found that autophagy helps to degrade fat in the liver.
This article originally appeared in the Summer issue of the Diabetes Research Center newsletter.We were looking at fat deposits in hepatocytes—liver cells—which is often a complication of diabetes," says Dr. Singh. In a 2009 study published in Nature, Dr. Singh and colleagues showed that inhibiting autophagy in mice caused their liver cells to accumulate fat—clear evidence that autophagy does indeed control fat levels in the liver. "We actually observed a vicious cycle," says Dr. Singh, "in which decreased autophagy causes livers to become fatty— and this accumulating fat makes things worse by further suppressing autophagy."
But Dr. Singh and his colleagues found that elsewhere in the abdomen—in fat tissue— autophagy actually helps to form fat tissue. When the researchers shut down autophagy in fat tissue, mice remained lean and protected against diabetes despite being fed a high-fat diet, since they now burned fat instead of storing it.
"These results were so exciting that we started thinking about what else autophagy might be doing," says Dr. Singh. So he decided to look at the brain—more specifically, at a specialized set of brain cells (hypothalamic neurons) that regulate how much animals eat by monitoring their nutrient intake.
Sure enough, Dr. Singh (now in charge of his own lab at Einstein) found that autophagy also occurred in these crucially important neurons. More specifically, when starvation switches on autophagy in these neurons, small fat droplets within the neurons are digested; this produces free fatty acids, which boost levels of a neuronal molecule that prompts the animal to begin feeding.
The next step was for Dr. Singh to use genetic engineering techniques to shut down autophagy in those "hunger neurons" of the brain. The result? Mice whose neurons could not activate autophagy following an overnight fast ate less than mice in which autophagy remained intact. Those important findings were published last year in Cell Metabolism, with followup work published in EMBO Reports this year.
"If we can identify the appropriate molecular targets and find the right drugs, we might be able to manipulate autophagy in an organ-specific manner to control obesity," says Dr. Singh. Promoting autophagy in the liver, he notes, could burn fat and prevent it from accumulating. By contrast, shutting it down elsewhere—in fat tissue and in nutrient-sensing neurons in the brain—could help curb appetite and keep us lean and healthy.
How does losing weight fight diabetes?
For overweight people with type 2 diabetes, losing 10 to 15 percent of total body weight can help lower blood sugar (glucose). That’s because being overweight causes a condition called insulin resistance, in which insulin that people produce—needed for moving glucose from the bloodstream and into cells—isn’t efficiently used by their bodies. So sugar levels in the blood become elevated, leading to type 2 diabetes.
For people who have type 2 diabetes, losing weight can help reverse insulin resistance: Their cells become more sensitive to insulin, allowing them to use insulin more efficiently. As a result, people with type 2 diabetes may be able to reduce—or even eliminate—the drugs they’re taking to normalize their blood sugar levels.