High-altitude metabolism lets mice stay slim and healthy on a high-fat diet

Apr 15, 2010

Mice that are missing a protein involved in the response to low oxygen stay lean and healthy, even on a high-fat diet, a new study has found.

"They process fat differently," said Randall Johnson, professor of biology at the University of California, San Diego, who directed the research, which is published in the April 15 issue of the journal . While their normal littermates , develop fatty livers and become resistant to insulin on a high fat diet, just like overweight humans do, the mutant mice suffered none of these ill effects.

The protein, an enzyme called FIH, plays a key role in the physiological response to low levels of oxygen and could be a new target for drugs to help people who struggle with weight gain. "The enzyme is easily inhibited by drugs," Johnson said.

Because the protein influences a wide range of genes involved in development, the scientists were surprised that its deletion improved health.

"We expected them to die as embryos," said Na Zhang, a graduate student in Johnson's lab and lead author of the study. "Then we saw they can survive for a long time."

"From the beginning I noticed that these mice are smaller, but not sick. These mice seem to be healthy," Zhang said. The lean mice have a high metabolism, and a common check for , a symptom of diabetes, revealed a super sensitivity to insulin.

"We fed the mice with a very high fat diet - 60 percent fat - just to see how they would respond," Zhang said. "Mutants can eat a lot, but they didn't gain a lot of weight. They are less fatty around their middles compared with their littermates."

Obese people develop a "fatty liver," and so did the wild type littermates. The fat mice also developed with elevated levels of the "bad" type, LDL. In lean mutants, LDL increased much less.

"All of these observations support that the modified mice have better metabolic profiles," Zhang said.

The genetic manipulations disabled the FIH gene entirely. "In every tissue, in every cell, the protein is gone," Zhang said. But the scientists wanted to know what part of the mouse physiology was responsible for the changes, so they created new mice in which the FIH protein was deleted only in specific tissues: the nervous system or the liver.

Mice that were missing FIH only from their nervous system showed most of the same effects. "But if it was only deleted in the liver, then no." Zhang said.

Though smaller, the mutant mice eat and drink 30 to 40 percent more than wild-type mice.

"Where do those calories go? To heat generation and an increased heart rate." Johnson said. They also breathe heavily compared with normal mice, taking in 20 to 40% more air. "This deep breathing is like exercise for them."

The FIH protein is part of a wide system that responds to low levels of oxygen. The mice behave as if they are breathing thin air. When people travel to higher altitudes, they breathe heavily for a few days, then adjust by producing more oxygen-carrying blood cells. "These never adjust to the apparent low oxygen," Johnson said. "They stay in this acute phase of hypoxic response their whole lives."

Explore further: How plant cell compartments change with cell growth

Related Stories

Secreted protein sends signal that fat is on the way

Dec 02, 2008

After you eat a burger and fries or other fat-filled meal, a protein produced by the liver may send a signal that fat is on the way, suggests a report in the December issue of the journal Cell Metabolism, a Cell Press public ...

Waistline growth on high-carb diets linked to liver gene

Dec 04, 2007

Experts have been warning for years that foods loaded with high-fructose corn syrup and other processed carbohydrates are making us fatter. Now, a University of Wisconsin-Madison study has uncovered the genetic basis for ...

Scientists reveal key enzyme in fat absorption

Mar 16, 2009

Scientists at the Gladstone Institutes of Cardiovascular Disease (GICD) have found that a key enzyme involved in absorbing fat may also be a key to reducing it. The enzyme, acyl CoA: monoacylglycerol acyltransferase 2 or ...

Recommended for you

How plant cell compartments change with cell growth

22 hours ago

A research team led by Kiminori Toyooka from the RIKEN Center for Sustainable Resource Science has developed a sophisticated microscopy technique that for the first time captures the detailed movement of ...

Plants can 'switch off' virus DNA

22 hours ago

A team of virologists and plant geneticists at Wageningen UR has demonstrated that when tomato plants contain Ty-1 resistance to the important Tomato yellow leaf curl virus (TYLCV), parts of the virus DNA ...

A better understanding of cell to cell communication

23 hours ago

Researchers of the ISREC Institute at the School of Life Sciences, EPFL, have deciphered the mechanism whereby some microRNAs are retained in the cell while others are secreted and delivered to neighboring ...

A glimpse at the rings that make cell division possible

23 hours ago

Forming like a blown smoke ring does, a "contractile ring" similar to a tiny muscle pinches yeast cells in two. The division of cells makes life possible, but the actual mechanics of this fundamental process ...

User comments : 0