Inhibiting an enzyme enables mice to stay lean on a high fat diet, without exercise

Eating a high-fat diet and staying lean without exercise is something that many people wish for. Now this dream is a reality, if you are, say, a genetically engineered mouse. Researchers at the University of California, Berkley, led by Dr. Hei Sook Sul, identified an enzyme that plays a key role in fat metabolism and when disabled, allowed mice to gorge on a high-fat diet without the consequences of weight-gain. Published in the January 11th issue of Nature Medicine, these findings might be an early step toward finding a treatment for some forms of human obesity.

The enzyme, called adipose-specific phospholipase A2 (AdPLA), is highly abundant in fat cells and triggers a cascade of events leading to an increase of prostaglandin E2 (PGE2), a molecule which suppresses fat breakdown. Cells that lack AdPLA have a higher rate of fat metabolism. The team knocked out the gene that codes for AdPLA in mice and compared them to a group of normal mice. Starting at three weeks of age, both groups were fed a high-fat diet and were allowed to consume as much food as they wanted. The results were astonishing. Although both groups ate similar amounts of food, the AdPLA knock-out mice weighed 39.1 grams by the end of their lifespan (64 weeks of age), which was only half the weight of the control mice, which averaged 73.7 grams.

Interestingly, the researchers found that the mice without AdPLA had the same number of fat cells but did not amass excess fat. The knock-out mice expended more energy and burnt more fat directly within their fat cells. Removing AdPLA resulted in unchecked amounts of fat breakdown regardless of how much food the mice consumed.

"We found significantly increased fatty acid oxidation [breakdown of fat] in adipocytes [fat cells] from AdPLA-null . compared with wild-type" the researchers noted in the paper,".indicating that, at least in part, increased fatty acid utilization within adipocytes contributed to the increased energy expenditure."

However, inhibition of AdPLA was not without consequences, as it led to a four-fold increase of liver fat content. Consequently, the researchers next plan to decrease the amount of AdPLA expressed in fat tissues rather than eliminate the enzyme altogether in attempt to preserve the obesity preventative outcomes while eliminating the undesirable secondary effects.

Written by: Tetyana Pekar

Edited by: Matthew Getz

Published by: Hoi See Tsao

Former JYI staff members have gone on to win Rhodes, Marshall, and Fulbright Scholarships, as well as NSF Graduate Research Fellowships and other graduate research funding.
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