Why are we So Fat?

The Baltimore Sun

In the global war on fat, just telling people to eat less and exercise more has proven to be an inadequate strategy. Despite an explosion of low-fat foods, diet regimes and public awareness campaigns, Americans and people in much of the rest of the industrialized world have continued to pack on the pounds.

"If you could fix this epidemic through behavior changes alone, that would be fantastic," said Dr. Mitchell A. Lazar, an obesity expert at the University of Pennsylvania. "But that has been very hard to do. To correct the problem we need more tools."

The new tools doctors are most eager for are effective drugs. Developing medicines to fight obesity and its ill effects, however, requires unlocking the still-mysterious cellular mechanisms by which fat harms people's health and leads to diseases such as diabetes and heart disease.

A team of researchers at the University of Maryland School of Medicine has made a discovery that provides insight into those mechanisms.

The group, which published its findings in the June issue of the American Journal of Physiology - Endochrinology and Metabolism, was led by Dr. Da-Wei Gong, an endocrinologist at the school.

What they found was omentin, a fat hormone that has a curious relationship with insulin, the key molecule in the obesity-related illness Type 2 diabetes.

In addition to possibly playing a role in the link between obesity and diabetes, omentin may also help determine whether an overweight person has a big belly or a big bottom.

The discovery comes a decade after experts first realized fat cells are more than microscopic gas tanks, storing fuel for future use. They are also tiny factories, spewing out hormones that alter the body's metabolism - often in harmful ways.

Scientists have identified various active molecules made by fat. The first was the hormone leptin, which was discovered in 1994 and is believed to act on the brain to suppress appetite. Animals and humans lacking leptin because of genetic aberrations become immensely obese.

Other hormones produced by fat, such as adiponectin, resistin and visfatin, appear to play a role in metabolism and to interact with insulin, a molecule that helps cells take in sugar.

Besides learning that fat produces hormones, scientists have more recently realized that not all fat is created equal.

Visceral fat, which collects under abdominal muscles and surrounds the liver and other internal organs, is believed to be a particularly bad actor. In contrast, subcutaneous fat, the kind that collects under the skin in other parts of the body, is less harmful.

"Apple-shaped" people, who tend to build up visceral fat, have a greater chance of suffering from heart disease and diabetes than "pear-shaped" people, who collect subcutaneous fat on their hips, thighs and buttocks.

Experts suspect that one or more hormones pumped out by the molecular factories in visceral fat cells might be troublemakers. If such a molecule could be linked to diabetes or heart disease, it might explain why visceral fat is so harmful.

Last year, a team of Japanese researchers appeared to be on the right track when they found a hormone they thought to be unique to visceral fat. They named it "visfatin," but the name proved inaccurate, after follow-up studies found the hormone was produced equally by subcutaneous and visceral fat.

The haystack

Meanwhile, the Maryland team, led by Gong, was studying fat from human cadavers and from monkeys, also trying to find new fat hormones. Gong analyzed more than 10,000 genes from the fat cells, looking for one that might produce a troublesome hormone specific to visceral fat.

In that haystack of possibilities the team zeroed in on omentin. "It jumped out at us," said Dr. Alan R. Shuldiner, one of the researchers, "as why one of the two fat depots is different."

The Maryland team wasn't the first to find the molecule. In 2001, another team of Japanese researchers found it was secreted in the human intestine and named it "intelectin," short for intestinal lectin.

The Maryland team found, however, that the hormone was produced almost entirely by visceral fat. "It does have some expression in the intestine," Shuldiner said. "But by far the majority is expressed in visceral fat."

They decided that omentin - from the omental tissue in the gut - was a better name for the molecule. They also found that it appeared to play a role in the workings of insulin, the key molecule in diabetes.

It appeared that they might have found a molecular connection between visceral fat and Type 2 diabetes.

Omentin, however, turns out to be an enigma. It is a molecule produced by harmful fat but appears to act on insulin in ways beneficial to diabetics.

"We initially assumed it was a bad thing," Shuldiner said. "As it turns out, it may be a good guy."

Insulin's job in the body is to shuttle sugar from the blood stream into cells where it is stored or used for energy.

Plenty of insulin is available in the blood of people who have Type 2 diabetes, but the cells refuse to respond to it. "It's like they just aren't answering the door," said Dr. Annabelle Rodriguez, a diabetes expert at Johns Hopkins Bayview Medical Center.

As a result, sugar levels soar in the blood while cells are starved of fuel. Over time this imbalance can result in blindness, nerve damage, and kidney and liver failure.

Surprise finding

Because visceral fat has been implicated in Type 2 diabetes, the Maryland researchers suspected omentin played a role in overweight people becoming insulin resistant. But to their surprise, they found instead that it enhances insulin activity, helping cells absorb sugar.

"On the surface it seems as if it's a paradox; you have a molecule doing good things but being produced by bad fat," Shuldiner said. "We don't really know if omentin is a good guy or a bad guy."

One role the hormone may play is in determining a person's shape. Whether someone looks more like an apple or pear could depend on omentin.

Most people are likely to gain visceral fat as they get older, and some races and families are prone to obesity-related illness.

One study, for example, found that Asian Indians are more likely to build visceral fat than Caucasians. They are also more likely to have Type 2 diabetes, as are African-Americans, Latinos, Native Americans, Asian-Americans and Pacific Islanders.

One theory proposed by the Maryland researchers is that some people may have a genetic predisposition to produce more omentin in their visceral fat cells.

That excess omentin would go to neighboring visceral fat cells and encourage them to turn sugars into fat. The person would be more likely to be overweight and more likely to have a bulging belly than a bulging bottom.

A person prone to stomach fat might in turn be prone to fat-related diseases such as diabetes and heart disease. "Where you store your fat," Shuldiner said, "is going to be very critical in determining what diseases you are prone to. The good news is that the visceral fat is the first to go with diet and exercise."

The bad news is that a complete understanding of how obesity relates to other diseases may be years away, and the problem is growing.

Over the past two decades the number of obese adults in the United States has grown to more than 60 million, according to the National Center for Health Statistics.

Globally, more than a billion people are overweight and 300 million of those people are obese, according to the World Health Organization.

Two studies published in the New England Journal of Medicine last month found that people who were even a few pounds overweight were more likely to die than people at a healthy weight.

Despite omentin's paradoxical interaction with insulin, the Maryland team and others hope the hormone's discovery is an important step toward understanding the molecular function of fat and developing drugs to fight its impact.

"We have some pretty good medicines for diabetes," Shuldiner said, "and then we have some pretty poor medications to treat obesity. It makes sense to me to find better ways to treat obesity."

chris.emery@baltsun.com

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