Researchers at the University of California, Berkeley, have identified a new enzyme that plays a far more important role than expected in controlling the breakdown of fat. In a new study to be published in the journal Nature Medicine, the researchers report that mice that have had this enzyme disabled remained lean despite eating a high-fat diet and losing a hormone that suppresses appetite.

 

The researchers say the discovery of the new enzyme within fat cells, a key regulator of fat metabolism and body weight, represents a “promising target in the search for a treatment for human obesity.”

 

The enzyme, adipose-specific phospholipase A2 or AdPLA, is abundant only in fat tissue. The enzyme sets off a chain of events that increases levels of a signaling molecule called prostaglandin E2 or PGE2, which suppresses the breakdown of fat. Mice without AdPLA have lower PGE2 levels and a higher rate of fat metabolism. When levels of PGE2 are decreased because of the lack of AdPLA, fat breakdown proceeds unchecked, resulting in leanness even in animals that eat all day long, the researchers say.

 

In the study, mice that had the gene for AdPLA expression knocked out were compared with a control group of normal mice. As soon as the mice were weaned at about 3 weeks of age, researchers began offering the two groups of mice as much high-fat foods as they would consume.

 

The enzyme did not appear to affect appetite since the two groups ate equivalent amounts, the researchers say. However, as the mice aged, the disparity in weight gain became clear. By 64 weeks of age—considered the twilight years in a lab mouse’s lifespan—the mice that lacked the AdPLA enzyme averaged only 39.1 grams, a weight more typical of a low-fat diet, while the control mice weighed in at a hefty 73.7 grams.

 

The missing AdPLA did not change the number of fat cells, but simply kept the cells from accumulating excess fat, the researchers report.

 

The researchers also examined whether loss of AdPLA could prevent genetic obesity in mice. They compared mice that lacked leptin, the hormone that signals when the body is full, with mice that lacked both AdPLA and leptin. Leptin-deficient mice are voracious eaters, typically consuming two to three times more food per day than normal mice, and they rapidly develop obesity.

 

In this study, leptin-deficient mice ate an average of 5 grams of food per day, while mice that lacked both AdPLA and leptin ate 7.5 grams. Typically, normal mice will eat only 2-3 grams per day. By 17 weeks of age, the leptin-deficient mice were already hitting the scales at 75 grams. In comparison, mice that lacked both AdPLA and leptin weighed just under 35 grams.

 

The researchers found that levels of AdPLA increase after eating to block fat breakdown, and decrease with fasting to allow fat breakdown to proceed efficiently. They also found that levels of AdPLA are higher in obese mice.

 

The finding is significant because obesity experts long assumed that the major players in controlling fat metabolism and body weight were primarily hormones that are secreted by different organs and glands and travel through the bloodstream to fat tissue. The new findings show that a large portion of the activity is occurring within the actual fat tissue.

 

“This means that local signals in fat tissue allow fat cells to directly regulate fuel provision for the body, which changes our fundamental understanding of how the body regulates fat breakdown,” says post doctoral student Maryam Ahmadian, one of the co-lead authors of the study. “We found that mice deficient in AdPLA expend more energy than normal mice, and they also burn more fat directly within fat cells.”

 

Previous discoveries in fat metabolism and appetite regulation have not always translated well from mice to humans. Although some people have mutations in the gene that codes for AdPLA, it remains to be seen what effect these mutations have in humans, the researchers caution. They also note that inhibiting the expression of AdPLA in mice led to greater insulin resistance and a four-fold increase in fat content in the liver. However, they say tests of liver function were largely normal.

 

Nevertheless, they believe that AdPLA may become an attractive target in developing a treatment to combat obesity. If excess fat can be burned before it escapes the fat cell, it can never get into the bloodstream to negatively affect other organs, such as the heart.