Beyond Calories: Molecule Ensures Healthy Immune Response to Daily Meal Pattern
For immediate release: May 3, 2007
|Gökhan Hotamisligil sketches a diagram
depicting how STAMP2 affects a cell.
Boston, MA - Too much food over time is bad for people's health. It has been shown that excess body fat, or even the wrong kinds of food, can fire up the immune system in harmful ways that lead to insulin resistance, type 2 diabetes, and heart disease. Yet, even day to day, the body must have a way to prevent this kind of an immune response after the nutrient onrush that follows each breakfast, lunch, dinner, and between-meal snacks.
Researchers at the Harvard School of Public Health have discovered a protective factor in mice that appears to coordinate normal metabolic and immune activity after meals. The molecule, known as STAMP2, is made mostly in abdominal fat, where it increases just after meals and drops in between. It appears to help fat cells cope with the nutrient onrush. The paper will be published in the May 4, 2007, issue of Cell. (http://www.cell.com).
Without STAMP2, even a seemingly harmless regular diet causes ailments often experienced by people who are overweight or obese - higher blood sugar, higher blood lipid levels, insulin resistance, fatty liver, and increased abdominal fat. This cluster of changes, also known as metabolic syndrome, elevates the risk of heart disease, type 2 diabetes, and other problems, including cancer. The researchers also found that without STAMP2, immune cells invade the deep belly fat surrounding the organs and unleash a chronic low-grade inflammatory response believed to promote complications of obesity in people. Mice with STAMP2 remained healthy with the same daily meals.
"The discovery here is a mechanism that controls the body from mounting an immune response to the normal range of fluctuations in nutrients brought on by eating," said senior author Gökhan S. Hotamisligil, chair of the HSPH Department of Genetics and Complex Diseases. "By pulling one plug, we can destroy the normal nutrient response system and channel these signals to trigger inflammation. It gives us a picture similar to what we see in obese persons en route to metabolic problems." The molecule discovered here helps ensure a healthy response to daily meals and snacks.
The results advance a growing field of research into the connections among obesity, diabetes, and inflammation, a field established principally by Hotamisligil's research. He and others have shown that extra body fat can secrete low levels of wound-healing molecules and stimulate pathogen-fighting immune cells that chronically interfere with normal metabolism and may also be involved in the onset of related complex metabolic diseases. Evidence is emerging that some foods may do a little bit of the same every day if, for example, a molecule like STAMP fails to work properly.
"It is well established that if you develop extra fat or consume a surplus of energy, then places in the body not normally considered part of the immune response start exhibiting stress and inflammation," said Hotamisligil, who has long postulated that nutrients and pathogens may cross paths in cells. "The critical question is, 'Why does this happen?' Or posed differently: ‘Why doesn't it happen under normal circumstances?'"
Hotamisligil and lead author Kathryn Wellen, former HSPH graduate student, reasoned that some molecular mechanism may work within the normal range of nutritional fluctuations to actively prevent an inflammatory reaction to food and ensure the flow of nutrients into the cells. This hypothesis was the focus of Wellen's thesis work under the guidance of Hotamisligil.
To address this postulate, they proposed a list of tests that this mystery molecule would have to pass. It would be found in tissue that takes in nutrients, such as fat cells. And it would respond to both nutritional and inflammatory cues. Finally, absence of the molecule would convert the tissue from normal to sick, impair normal cellular metabolism, and disrupt metabolism throughout the body.
Candidates popped up in extensive gene expression analysis of 30,000 molecules comparing the fat of genetically obese mice treated with an anti-diabetic drug to the fat of mice deficient in an inflammatory molecule linked to insulin resistance. One factor, STAMP2, was suppressed in both scenarios, and it proved to be an exciting molecule. Until this time, little was known about the molecule STAMP2. Coincidentally, a visiting researcher in the Hotamisligil lab at the time, co-author Fahri Saatcioglu, originally had discovered STAMP2 in his Norwegian lab while looking for androgen-response genes in the prostate. "Having Fahri on board gave great momentum to our studies," noted Hotamisligil.
In further studies, Wellen and her colleagues found higher levels of STAMP2 in the visceral fat surrounding organs deep within mice bellies, the riskiest kind of fat in people. In experimental models, STAMP2 levels increased after eating and decreased after several hours of fasting. In two obese mouse models, this pattern of nutritional regulation of gene expression ceased when the mice became fat.
In order to prove the hypothesis, the investigators needed to create a new genetic animal model from which they removed the STAMP2 gene. Four more years of experiments showed that mice missing STAMP2 had inflammatory responses and metabolic problems similar to obese people.
"Under normal conditions, the function of STAMP2 may be invisible," said Wellen, now a postdoctoral fellow at the University of Pennsylvania School of Medicine. "The metabolic functions and fat cell inflammation is completely in check. It helps to maintain the status quo."
Now that the existence of this mechanism has been established, Hotamisligil hopes to learn more about how it works and if such knowledge could lead to the identification of people at risk for diabetes and heart disease and to the development of drugs that help reduce the complications of obesity.
"Coordinated Regulation of Nutrient and Inflammatory Responses by STAMP2 Is Essential for Metabolic Homeostasis," Kathryn E. Wellen, Raquel Fucho, Margaret F. Gregor, Masato Furuhashi, Carlos Morgan, Torstein Lindstad, Eric Vaillancourt, Cem Z. Gorgun, Fahri Saatcioglu, and Gökhan S. Hotamisligil, Cell, online May 3, 2007, Noon ET.
Support for this study was provided by grants from the National Institutes of Health, Norwegian Research Council, and Norwegian Cancer Society.
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