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Pass another double-bacon cheeseburger! These mice can't get fat
Really. They don't get diabetes either, even if you stuff them with high-fat feed.

That's the medical meal described in a recipe just published by James Ntambi and colleagues from the University of Wisconsin-Madison.

The researchers removed the SCD-1 gene, which Ntambi identified as a lowly graduate student in 1988. SCD-1 makes an enzyme that inserts a double bond into an unsaturated fatty acid. The result is a saturated fat, which can be stored in the rodent equivalent of spare-tire bulge.

Now, when you and I leave one element out of a recipe, it's usually a disaster. Forget the chilies, and you might as well forget the enchilada. Forget the yeast, and your bread may be mistaken for a leaden Frisbee.

But deleting SCD-1 from the recipe proved to be some kind of wonderful for Ntambi's mice: They stayed lean. Their blood sugar was lower than normal animals that ate the same high-fat stuff, indicating that they did not have adult-onset or type II diabetes which affects 17 million Americans and is a major element of the growing wave of obesity.

The fat mouse has a working gene for SCD-1, an enzyme that helps convert fat into a form that can be stored. The skinny mouse ate essentially the same diet, but was missing the SCD-1 gene. Photo by Jeff Miller. Copyright (c) 2002 The Board of Regents of the University of Wisconsin System.

Burning out
There is, of course, a glitch. We'll get to that in a minute. But first, let's sift and stir the new recipe.

The new finding, said Ntambi, provides insight into the central genetic mechanisms that underpin diet and metabolism, and suggests the possibility of devising drugs to protect against obesity and diabetes.

Ntambi, a professor of biochemistry and nutritional science at UW-Madison, collaborated with Alan Attie, also a professor of biochemistry, said the experiment flopped, in a sense. "The idea was to make them fat," Ntambi said, "but the mice lacking the SCD-1 gene never got up there despite a diet that contained nearly 15 percent fat. What we found is that when you feed these animals a high-fat diet for several weeks, they fail to accumulate fat over time."

The animals without SCD-1 consumed more oxygen, indicating that their metabolisms were cranking faster than normal animals. They were burning fat rather than storing it.

The work reinforces a recent study showing that the removal of SCD-1 compensates for the absence of leptin, a hormone that's normally essential for regulating body weight.

The absence of SCD-1 seems to have systemic effects: Fat does not accumulate in the liver or other tissues where it normally would gather and contribute to the health woes associated with diet and obesity, said Ntambi.

Instead, the excess fat seems to be metabolized: "We have biochemical evidence that the mice burn the excess fat," said Ntambi.

Attie noted that while the surface effects of removing the SCD-1 gene are not entirely unique, the model offers a glimpse into the metabolic mechanisms that underpin those effects: "The fact that you're increasing metabolic rate as a result (of knocking out the gene and its enzyme products) is really interesting."

Recipe for diabetics
The SCD-1 deletion activates genes that are known to increase fat metabolism. It also deactivates genes that help store fat.

The absence of the SCD-1 gene also seems to protect against diabetes by keeping glucose levels in the blood low. "These animals are more insulin-sensitive and don't become diabetic," says Ntambi. "After eating, glucose levels rise, but within a very short time the glucose goes down and stays down."

Control animals, which still had the SCD-1 gene, have higher blood glucose levels for longer periods of time when fed the same rich diet.

"All of this goes hand in hand," said Ntambi. "Most people who are diabetic have the condition due to the amount of fat. That's what causes insulin resistance and keeps glucose levels in the bloodstream high."

A better understanding of the metabolic processes may allow the development of drugs that interfere with the biochemistry of obesity. Such drugs would be important for public health: the U.S. Centers for Disease Control and Prevention estimates that 20 percent of Americans suffer from obesity.

What's the scratch - er, catch?
Mice totally lacking the SCD-1 gene are normal in most respects, but they do have weird hair and scratchy eyelids. The reason? The fat synthesized with the help of SCD-1 is needed to lubricate fur and eyelids. The fur dryness "is caused by a lack of oil in hair follicle," says Ntambi. "There's a similar problem on the eyelid. It doesn't synthesize fat, which lubricates the cornea for blinking."

You might think that's a recipe for constant scratching, but Ntambi says mice with mutations in only one of the two strands of DNA seem fine in this respect, "but still have the metabolic advantages." A drug that works on the SCD-1 pathway, he says, "could be titrated [metered out] to control this problem."

"I'm very optimistic," says Ntambi, "but things always go wrong along the way" between biochemical discovery and drug treatment. "We never thought SCD-1 would be a central enzyme in regulating metabolism. Here's the promise - you could eat a lot of food and not gain weight!"

-- David Tenenbaum

BIBLIOGRAPHY
Loss of Stearoyl-CoA Desaturase-1 Functions Protects Mice Against Adiposity, James Ntambi et al, PNAS Early Edition (online), Aug. 12, 2002.

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