Fat chance: the biology of obesity

Image: Diagram of how insulin aids glucose absorption

How insulin aids glucose absorption. When no insulin is present, insulin receptors on the cell surface are inactive, and glucose (shown in dark gray) remains in the blood. But when insulin enters the bloodstream, the insulin receptors activate signals within the cell that allow glucose to enter via transporters such as GLUT4.

Image: John MacNeill

June 22, 2005

Tags: Lodish LabProtein Function

Imagine this public-health drama as a film with two parallel plot lines.

Here’s the first plot line: The U.S. has a problem, a big problem. We’re increasingly becoming a nation of overweight—and often downright obese—people. Just look at the numbers. Statistics from 1985 show that less than 10% of the populations of New York and California qualified as being obese. Fast forward to 2001, and that number jumps all the way to 24%.

The second plot line unravels another drama: The onslaught of type 2 diabetes. This disease, afflicting nearly 10% of adults and a rapidly increasing number of children, is the leading cause of blindness and kidney failure, and ranks sixth on the list of killers. And the number of cases is soaring.

You’ve probably guessed the first plot twist: Both stories star the same villain.

While obesity plays a big role in other diseases ranging from cardiovascular disease to cancer, it tracks particularly well with the epidemic of diabetes. The state of Mississippi offers one telling example. While the rates of obesity there climbed from ten percent to over 25% during the 1990s, rates of type 2 diabetes climbed from 6% to over 10%.

In a Supersized nation where Burger King’s latest breakfast sandwich weighs in at 730 calories and 47 grams of fat, more and more people have trouble squeezing their stomachs behind the steering wheel as they head over to the drive-through.

But the plot thickens yet again: Advances in medical understanding of the biology of obesity offer hope for a happy ending.

As these twin epidemics explode, so has our knowledge of the key molecules and mechanisms responsible for giving fat a bad name—findings that many pharma companies are now trying to exploit with anti-obesity therapies.

Harvey Lodish, a Founding Whitehead Member and professor of biology at MIT, has pioneered this field. Lodish opened up the field of glucose transport regulation by cloning the first protein that transports this sugar across cell membranes. He also has been a leader in studying the hormones that fat cells secrete, comments diabetes researcher Jeffrey Flier of Harvard University.

The Lodish lab has helped to reveal why obesity is not only so toxic to an organism but also why it is so correlated with type 2 diabetes.

Shuttling sugar

Not all diabetes is related to obesity. Type 1 diabetes, often referred to as juvenile diabetes, has nothing to do with body weight. Rather, it’s a condition in which the immune system attacks the insulin-producing cells in the pancreas, causing blood sugar levels to skyrocket. In type 2 diabetes, often called adult-onset diabetes, the cells in muscle and fat tissue start becoming resistant over time to the signals that insulin sends. Once again, blood sugar levels skyrocket.

It’s been known for about 80 years that insulin is the hormone chiefly responsible for regulating glucose, the sugar in your blood that gives you energy. In fact, insulin is the first biotechnology product ever, manufactured in the 1920s to treat type 1 diabetes.
“Basically, insulin is part of a regulatory circuit,” says Lodish, much of whose work has focused on the exact signaling process by which insulin communicates with cells.

Here’s how it works:

Whenever you eat or drink, your digestive system releases glucose into your bloodstream. But the glucose can’t make it into your cells without help from insulin.

As the glucose level in your blood mounts, certain cells in your pancreas start producing insulin and releasing it into your bloodstream. The insulin molecules make their way to muscle cells, where they bind to receptor proteins on the surface and send signals to proteins deep in the cytoplasm called glucose transporters—a class of proteins that was first identified in Lodish’s lab in 1985.

Insulin lets these proteins know that there is a crowd of glucose molecules outside the cell eager to get in. The glucose transporters wake up from their cytoplasmic slumber and travel to the cell surface. Here, they merge into the cell surface membrane and morph into a kind of trap door, allowing individual glucose molecules to pass through one at a time into the cell.

But in obese people, this entire process begins to break down. “The insulin signal is sent, but the transporters respond sluggishly,” says Lodish. “Eventually, they barely respond at all.”

If glucose stays at high levels in the blood, diabetes sets in, with all its nasty complications. As Lodish describes it, though, type 2 diabetes is not so much a disease like lung cancer or Parkinson’s. Rather, it’s a cluster of symptoms that in many cases can be eliminated through diet and exercise. When the symptoms vanish, the person is technically no longer a diabetic.

So the key to understanding this condition is located squarely in the plump center of the fat cell.

Size matters

For many years, fat cells were seen simply as cells that were. . .well. . . fat. That is, nothing more than passive repositories of triglycerides, the chief component of fats and oils. But that assumption took a hit in 1994 when Rockefeller University researcher Jeffrey Friedman discovered a hormone called leptin.

Studying mice that were genetically modified to be obese, Friedman found that leptin acts as a sort of thermostat for fat. When the mice ate too much, fat cells released leptin into the brain, where it would release a series of signals dictating that enough’s enough.

Further studies showed that mice who were deficient in leptin couldn’t stop eating and would thus become grossly obese. Once they were administered the hormone intravenously, their appetites returned to normal.

As it turns out, a small percentage of people are leptin-deficient and can be treated the same way. Undoubtedly, leptin is a “good” hormone.

But here’s the real kicker: Friedman had found that leptin was produced by fat cells. So fat cells were no longer seen as inert units for triglyceride storage. They were active players secreting important metabolic hormones.

The following year, the Lodish lab made an equally startling discovering when it found another fat-cell-secreted hormone called adiponectin, which acts in concert with insulin in helping the cells to absorb glucose from the blood. Adiponectin also helps the body to burn off fat and sugar by stimulating the same chemical pathway that is activated when we exercise.

“Clearly,” says Lodish, “adiponectin is a good thing to have.”
The real power of adiponectin became clear in a paper that Lodish and co-workers published in the journal Proceedings from the National Academy of Sciences in 2001. Here, the researchers studied a group of mice that had been made obese through what Lodish refers to as a “cafeteria diet.”

A cafeteria diet is exactly what it sounds like. These mice were fed all the butter and sugar they wanted—and their desire knew no limit.
Once the mice were suitably obese, Lodish and his team injected them with adiponectin. The mice in turn increased their “burning” of the stored fat and lost weight—results that appeared to be almost miraculous.

“We tried to publish this in one of the major journals but couldn’t because the reviewers simply didn’t believe it,” Lodish recalls. “The fact that injecting adiponectin caused these mice to increase the burning of fatty acids was just too startling. Once we got it published I had to keep reminding the media over and over again how mice aren’t people. Many scientists didn’t believe our work until it was confirmed by two other labs the following fall.”

Adiponectin is a great hormone to have in abundance, and it’s a terrible hormone to lack. Rare genetic conditions that cause adiponectin deficiency may cause diabetes and heart trouble.
But here’s where things get counterintuitive.

If leptin and adiponectin are manufactured by fat cells, and if having them in abundance is beneficial, then doesn’t it stand to reason that the bigger you are, the more of these hormones you produce, and thus the healthier you should be? Isn’t there some kind of bigness benefit?

Before you reach for those Super-sized fries, the answer is no.
As it turns out, obese people become resistant to leptin. What’s more, fat cells in obese tissue start to underproduce adiponectin, so obese people become deficient in this crucial hormone.

Inflammatory news

Now things get worse. Recent studies comparing fat tissue from normal-weight people and from obese people have provided further evidence that not all fat cells are created equal.

In people with normal weight, fat tissue contains precisely what you’d expect to find: lots of fat cells (known as “adipocytes” in the scientific parlance). But in obese people, fat tissue is loaded with cells called macrophages, cells that normally ingest pathogens and other foreign materials. When they ingest these foreign objects, they release inflammatory hormones that alert the immune system, hormones such as macrophage-produced tumor necrosis factor alpha (TNFa), a hormone that is elevated in arthritis and is also related to cancer and other conditions.

This makes perfect sense, because obesity is essentially an inflammatory disease, comments Gökhan Hotamisligil, professor of genetics and metabolism at the Harvard School of Public Health. “Excess calories affect the fat cells in such a way that they mount an immune response,” he says. “You’re activating the immune system without a legitimate pathogen,” Hotamisligil continues. “You’re constantly activating your immune system at a low level in such a way that it releases chemicals that start contributing to inflammation.”

Obesity, then, causes stress, which alerts the immune system, which leads to the production of inflammatory mediators that interfere with the function of other metabolic pathways, which in turn causes stress.

“It soon turns into a vicious cycle,” says Hotamisligil.

Lodish points out that the inflammatory hormone TNFa, which is found abundantly in fat tissue from obese people, blocks the expression of many fat cell genes that are vital for insulin action, including adiponectin (this is why obese people have less adiponectin in their blood).

Hong Ruan, a postdoctoral researcher in Lodish’s lab, found that high levels of TNFa alter gene expression in such a way that fewer fatty acids are stored in the fat cells. Instead they are released into the blood, creating insulin resistance in the muscle.

“This process goes on for many years, so eventually you wind up with low levels of adiponectin, high levels of fatty acids in the blood, and high levels of glucose in the blood,” says Lodish.
But how might all these new insights into the biology of obesity lead toward therapies?

Of mice and medicine

Hanging on the wall of Lodish’s office, near copies of the bestselling molecular biology textbook he co-authored, is Whitehead’s patent on the hormone adiponectin, the molecule responsible for making those obese cafeteria-diet mice lean and mean.

While Lodish may be a hero to the world’s millions of rodents, the hormone has yet to work the same kind of magic in people. Serono, the world’s largest biotech, ended up acquiring rights to the molecule. And it’s apparently hard at work trying to develop an adiponectin product that can be injected into people—perhaps the closest we could ever come to realizing every couch potato’s fantasy of losing weight simply by taking your medicine.

We’ve recently discovered seven other molecules in the genome that work the same way as adiponectin,” adds Lodish. He just signed a licensing agreement with Wyeth Pharmaceuticals to work on these hormones.

The research joins hundreds of other projects shooting for weight-reduction drugs. And even though adiponectin activates the very same metabolic pathways stimulated by exercise, it probably won’t be a chocoholic’s dream come true. The molecular complexities of fat tissue and the difficulties of production and delivery still pose serious obstacles.

And despite all the research advances, obesity is still in many respects uncharted terrain.

“We don’t even know yet the location of the genes that very likely make people susceptible to obesity,” says Harvard’s Flier. “These genes could be active in the brain, or in the fat cells, or in the muscle cells, or really everywhere.” Flier believes that the answer most likely will come from large-scale population studies.

Will there ever be a “cure” for obesity? “It’s really too early to say,” says Lodish. “I doubt a single molecule will ever do the trick. But one might help reduce the problem, especially in the early stages.”

In the meantime, here’s his prescription: “Diet and exercise.”

Written by David Cameron.

This article first appeared in the Spring 2005 issue of Paradigm magazine.

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