Harvard Public Health Review
Winter 2005

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Panic in the Endoplasmic Reticulum

New clues to how obesity wreaks the metabolic havoc of type 2 diabetes

The ancients knew well the ravages of diabetes--"the melting down of flesh and limb into urine," as a physician described it 2,000 years ago, succinctly capturing the weight loss, frequent urination, and complications such as limb amputations. But they were without clues to its cause.

Scientists are still working to untangle the roots of type 2 diabetes, which accounts for more than 90 percent of diabetes cases. Overweight and obesity have long been known to be a major--and modifiable--risk factor for the disease, but precisely how excess fat does its dirty work has been hard to pin down.

Type 2 diabetes affects an estimated 18 million Americans, and its grim complications kill more than 200,000 in the U.S. a year. The disease has exploded in developed countries around the world, mainly as a consequence of rising obesity; by one estimate, 150 million people suffer from the disease. More than four out of five are overweight.

Tracing the obesity-diabetes connection is a major research interest of Gökhan Hotamisligil, chair of the Department of Genetics and Complex Diseases. This pediatrician-turned-basic-scientist studies a group of conditions known as "the metabolic syndrome" that often occurs in obese people: high blood pressure, insulin resistance, cholesterol abnormalities, heart disease, and type 2 diabetes. Insulin resistance is a prelude to diabetes, wherein cells become deaf to the signals of insulin, and consequently can't import vital fuel in the form of glucose (sugar), which remains in the blood to cause damage.

Alarmingly, the rising prevalence of metabolic disease has reached an estimated 20 to 25 percent of the U.S. population, according to the American Heart Association.

In a recent set of experiments, Hotamisligil reports finding what he believes is the critical "missing link" in a biochemical pathway through which excess body fat triggers a destructive chain of events leading to inflammation, insulin resistance, and diabetes. Some of the new molecular culprits that have emerged, says Hotamisligil, could become targets for highly specific drugs aimed at slowing or halting the disease. "I'm extremely excited about the potential therapeutic applications," he says.

The gist of the discovery is that diabetes begins when fat cells are put under severe stress by their own sheer mass and demands on the cells' operating systems. The crisis sends the cells into an all-hands-on-deck distress signal aimed at survival. Prompted by the alarm, a master switch turns on a cascade of activity that, among other effects, suppresses normal insulin activity and spawns an inflammatory reaction that eventually inflicts damage on many organs. A major player in this pathway is a gene called JNK that Hotamisligil discovered in 2002: it is directly involved in causing insulin resistance.

"One of the major questions in diabetes has been: How is obesity sensed by the body?" says Hotamisligil. In the paper published in Science in October, he says, "We provide an answer to this question. I believe it is one of the biggest findings in this area."

HSPH fellows Umut Ozcan and Qiong Cao are the first authors. Laurie Glimcher, the Irene Heinz Given Professor of Immunology in the Department of Immunology and Infectious Disease, is also a co-author.
The backdrop to these new findings is a wave of discoveries over the past decade that fat cells are far more than just storage bins for energy. They actively secrete chemical messengers, some of which advise the brain on the state of energy balance in the body. Other fat-cell secretions rile up the immune system, igniting inflammation. (Hotamisligil identified one of the first fat-derived immune instigators, tumor necrosis factor a, in 1991 as a post-doctoral fellow in the laboratory of Bruce Spiegelman at the Dana-Farber Cancer Institute.)

Inflammation, a response by immune cells to invading microbes or tissue injury, becomes chronic in obese people, simmering like a fire in a coal mine. Over time, this misguided attack on the body itself sends legions of inflammatory cells coursing through the circulatory system, damaging blood vessel linings, bringing on atherosclerosis and impaired blood flow, and setting the stage for devastating complications such as heart and kidney disease, blindness, amputations, and stroke.

What's been lacking is a detailed, molecular blow-by-blow of how fat incites cells to undergo diabetic changes. The new insight of Hotamisligil's is that the problems first appear inside an extensive system of folded membranes and tubules in cells called the endoplasmic reticulum, or ER.

The ER is the factory where amino acids specified by the cell's DNA recipes are assembled into proteins. The ER also processes or "folds" the proteins into a complicated, three-dimensional configuration and dispatches them to destinations within the cell. When protein and lipid traffic is high, the ER can be a very busy place.

Under adverse conditions, the ER's capacity can be strained to the breaking point, threatening to shut down the cell permanently. The stressors may be viral infections (creating a sudden demand for more proteins), lack of nutrients, a shortage of oxygen, or mutations.

This urgent situation, called ER stress, can flare up in fat cells and is the fundamental trigger that ignites the metabolic havoc of type 2 diabetes, according to Hotamisligil.

The fat cell "is a big, spherical cell with a heavy burden that even under the best of conditions uses up all its excess capacity to be able to run its business," Hotamisligil says. "The fat cell is really susceptible to any additional stress, and plenty of it comes with obesity," when the cell, asked to hold even more fat, is stretched to the limit.

Supporting Hotamisligil's hypothesis, experiments with isolated cells and obese mice showed that ER stress leads to activation of a number of genes and proteins previously implicated in insulin resistance and inflammation. And in a part of the work with promising implications for new treatment, the scientists found that a protein called XBP-1, originally cloned by Glimcher, serves as a master switch in ER stress conditions that can turn the inflammation-related genes on and off. Mice with inactivated XBP-1 were highly prone to diabetes, while those given an overactive XBP-1 were protected from it.

Manipulating XBP-1 with drugs "looks like a good way to interfere with diabetes," he says.

As determined as he was to discover the new molecular link, Hotamisligil is equally concerned about the rise of obesity and type 2 diabetes as a global public health problem. The diseases have taken hold in both developed and, increasingly, developing countries over the past half-century. Why? There's strong evidence that as conditions have changed from food scarcity to abundance, and lifestyles have become much more sedentary, the way humans live has gotten sharply out of sync with 2.5 million years of evolution.

"For any organism to be successful, it has to resist starvation, and also mount an immune response to resist pathogens," Hotamisligil says. So our genetic program has evolved over millions of years to create a highly efficient metabolism that fosters storing a strategic reserve of energy as fat, and an alert, responsive immune system to combat infections.

These two response systems are now highly integrated and influence each other. But these traits have become counterproductive: In an era of plentiful food and less physical activity, they lead to obesity and insulin resistance. And the protective immune system can turn traitor, unleashing tissue-damaging inflammation when it overreacts to toxic chemicals and other stresses of modern life.

While probing the molecular nitty-gritty of the health-eroding conditions of the metabolic syndrome, Hotamisligil has in mind a much greater, overarching goal: teasing apart the dizzyingly complicated interplay of genetics and environment that cause the metabolic diseases, and possibly other complex diseases such as atherosclerosis and cancer. When the scientist shows a slide of the theoretical interaction of many genes and environmental factors among themselves and each other, "it's an almost infinite number that will have to be decoded," he says.

Decoded, that is, into quantifiable risk estimates for individuals. It conjures up visions of the world's largest spreadsheet--one that would list each of John Smith's myriad inborn predispositions and lifestyle factors. Ultimately, the hope would be to create for every person a profile of these genetic vulnerabilities and environmental exposures. For example, "A person who has the capacity to tolerate four units of stress but is routinely exposed to five units will always be under stress," says Hotamisligil. Such a person would need to make some changes in lifestyle, but also could be "bumped a little bit in the right direction" by drugs.

Extending this idea to large numbers of people might seem a hopelessly massive and complicated project. Not to mention the likelihood that pharmaceutical companies would have to make a great variety of drugs to fill these personalized niches. Yet Hotamisligil is undaunted.

"I guess it's my personality," he shrugs. "I am a pathologically optimistic person: I think that the outcomes will be positive and build my life around the positive angle, and it's working for me." He's been through the territorial, dog-eat-dog gauntlet of academic medicine and believes that the more collegial atmosphere of the School makes large ambitions possible, although his main focus will remain on the mechanistic aspects.

"Other people get excited and they join forces--most of my colleagues are very positive people," Hotamisligil says. "There is no reason to be scared of thinking about things and sharing your thoughts."

Richard Saltus has been a science and health reporter for the Boston Globe, the San Francisco Examiner, and the Associated Press.

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