A US study showed that switching off an enzyme that plays an important role in the breakdown of fat in mice helped them to remain lean even when they ate a high-fat diet. They also showed switching off the enzyme in mice that had no appetite-suppressing hormone (this normally signals when the body is full) had the same effect, the mice stayed lean.

The study was the work of lead investigator Dr Hei Sook Sul, University of California (UC) Berkeley professor of nutritional sciences and toxicology, and colleagues, and is published in the 11 January issue of Nature Medicine.

Sul said:

“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.”

The enzyme, which is abundant only in fat tissue, is called adipose-specific phospholipase A2 (AdPLA), it is encoded by the gene Pla2g16, also called HREV107. AdPLA triggers a sequence of events that increases prostaglandin E2 (PGE2), a signalling molecule that stops fat breaking down. Mice that don’t have AdPLA have less PGE2 and a higher rate of fat breakdown.

Co-author Dr Robin Duncan, a post-doctoral fellow at UC Berkeley, explained:

“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.”

For the study, Sul and her colleagues knocked out the gene that codes for AdPLA in one group of mice and compared them to a control group of normal mice. When they reached 3 weeks old, the mice were weaned and given high-fat, tasty food, from which they could eat as much as they wanted.

The researchers noted that knocking out AdPLA did not affect appetite because both groups ate similar amounts: they both gorged on the same high fat food. But, as the mice got older, a gap appeared in their weight. When they reach their 64th week, toward the end of a lab mouse’s lifespan, the mice that had no AdPLA averaged 39.1 grams in weight, while the control mice averaged 73.7 grams.

Sul and her colleagues also found that the mice without AdPLA still kept the same number of fat cells, but they just didn’t accumulate excess fat.

In the next stage of the experiment, the researchers examined whether knocking out AdPLA could prevent genetic obesity in mice. Mice that don’t have a hormone called leptin, which signals when the body is full, tend to eat two to three times more food than normal mice and become obese very quickly. A normal mouse typically eats 2 to 3 grams of food a day.

The researchers compared two groups of mice: one (the controls) lacked leptin, and the other also lacked leptin and AdPLA. They found that the mice without leptin ate an average of 5 grams of food a day, while the mice that lacked both leptin and AdPLA ate 7.5 grams. As they reached 17 weeks of age, the mice that lacked leptin weighed an average of 75 grams, but the mice that lacked leptin and AdPLA weighed just less than 35 grams.

On studying AdPLA further, Sul and colleagues found it goes up after eating, which prevents fat breaking down, and it goes down during fasting, which allows fat to break down. They also found that obese mice had higher levels of AdPLA.

Co-author Maryam Ahmadian, a graduate student at UC Berkeley said:

“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.”

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

They also found that reducing AdPLA in the mice led to greater insulin resistance and their liver fat quadrupled, but when tested, their livers were mostly normal.

A main function of fat tissue is to release fatty acids from stored fats so that other tissues can use them as an energy source. Before this discovery, scientists believed that the endocrine system played the major role in controlling fat breakdown and body weight, where hormones would travel to fat tissue from various organs and glands via the bloodstream and do their work there.

But this study shows that much of the work is done by agents already in the fat tissue, through the autocrine (signals acting in the same cell) and paracrine (signals acting on neighbouring cells) actions of PGE2.

But Sul and her colleagues were also cautious to point out that findings about fat metabolism and appetite control in mice don’t always translate to humans. Humans can have mutations of the gene that codes for AdPLA, but until we study them, we won’t know if they have the same effect as in the mice.

However, they suggested that AdPLA may be a useful target for new obesity treatments, explaining that if you can get the excess fat to burn off before it even leaves the fat cell, it can’t then travel to other organs like the heart and do damage there. As Duncan explained:

“We believe that the effects in the liver are due to the extremely high rate of fat breakdown and drastic leanness in these mice, so we are looking to see if reducing rather than completely eliminating AdPLA can provide effective protection against obesity without secondary effects.”

The study was supported by grants from the US National Institutes of Health, the Natural Sciences and Engineering Research Council of Canada, and the Canadian Institutes of Health Research.

“AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency.”
Kathy Jaworski, Maryam Ahmadian, Robin E Duncan, Eszter Sarkadi-Nagy, Krista A Varady, Marc K Hellerstein, Hui-Young Lee, Varman T Samuel, Gerald I Shulman, Kee-Hong Kim, Sarah de Val, Chulho Kang, Hei Sook Sul.
Nature Medicine 11 Jan 2009.
DOI: 10.1038/nm.1904

Click here for Abstract.

Sources: University of California Berkeley, journal abstract.

Written by: Catharine Paddock, PhD