Obesity Enzyme Knockout Keeps Mice Lean

Left: A mouse lacking leptin; Right: Normal mouse.

Researchers at the University of California, Berkeley, have identified a new obesity enzyme that plays a far more important role than expected in controlling the breakdown of fat. They report that mice with this enzyme disabled ("knocked out") remained lean despite eating a high-fat diet, even when they lack a hormone, leptin, that normally suppresses appetite (see figure right).

"We have discovered a new enzyme within fat cells that is a key regulator of fat metabolism and body weight, making it a promising target in the search for a treatment for human obesity," said Hei Sook Sul, UC Berkeley professor of nutritional sciences and toxicology. Sul's research team includes the three co-authors of the paper, Kathy Jaworski, Maryam Ahmadian, and Robin Duncan.

The obesity enzyme, called adipose-specific phospholipase A2 (AdPLA), is abundant only in fat tissue. It sets off a chain of events that increases levels of a signaling molecule called prostaglandin E2 (PGE2), which suppresses the breakdown of fat. Mice that lack AdPLA have less PGE2 and higher rates 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," said co-lead author Duncan.

In the study, mice with the gene for the AdPLA obesity enzyme knocked out were compared with normal mice. As soon as the mice were weaned at about 3 weeks of age, researchers began offering the two groups of mice all the yummy, high-fat foods they could eat.

The obesity enzyme didn't affect appetite. Both groups ate the same amount. However, as the mice aged, a difference in weight gain became clear. By 64 weeks of age -- considered the twilight time of a mouse's life -- the mice lacking the AdPLA obesity enzyme averaged only 39.1 grams, a weight typical of a low-fat diet. But the control mice weighed a whopping 73.7 grams.

The missing enzyme didn't change the number of fat cells. It simply kept them from accumulating excess fat.

The researchers also studied whether loss of AdPLA could prevent genetic obesity in mice. They compared mice lacking only leptin, the hormone that signals when the body is full, with mice lacking both AdPLA and leptin. Leptin-deficient mice are voracious eaters and pig out on an ongoing basis, typically consuming two or three times as much food as normal mice. And, of course, they pork out without delay.

The researchers found that 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 -- that is, half again as much as the already extremely piggy leptin deficient mutants. Normal mice typically eat only 2-3 grams per day. So these leptin-AdPLA double mutants were triply piggy, eating three times as much as a normal mouse. And yet at 17 weeks of age, they weighed a slim 35 grams! At the same age, however, mice that lacked only leptin tipped in at 75 grams, twice the weight of a normal mouse.

AdPLA levels increased after eating (presumably to block fat breakdown), and decreased with fasting (to allow fat breakdown to proceed). Levels of AdPLA were higher in obese mice.

"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," said Ahmadian. "We found that mice deficient in AdPLA expend more energy than normal mice, and they also burn more fat directly within fat cells."

Before this paper, the assumption had been that endocrine factors, primarily hormones, played the lead role in controlling fat metabolism and body weight, primarily hormones.

The new findings show a large portion of the action takes place within the fat tissue itself.

The findings of this study make AdPLA an attractive target for developing treatments to reduce obesity. If excess fat can be burned before it even escapes from fat cells, it can never get into the bloodstream to negatively affect other organs, such as the heart.