HSPH Scientists Illuminate Pathways Linking Fat and Disease

Across the nation and in much of the world, a rising tide of obesity-related ailments such as Type 2 diabetes and cardiovascular disease poses an enormous public health threat. The "metabolic syndrome" of overweight, insulin resistance or diabetes, out-of-whack blood lipids, and high blood pressure now affects roughly 25 percent of Americans, putting them at risk for disabling complications and premature death.

Persuading people to lead healthier lifestyles is crucial. But an understanding of the rather murky biological links between obesity and its health-endangering consequences is also urgently needed to create more-effective medical treatments and preventive measures. Public health needs bench science to help control such a population-wide epidemic, and scientists at HSPH have been dissecting some of the key biological circuits through which obesity and high-fat and high-carbohydrate foods do their mischief.

The general scenario is that excess fat in the diet and stored in fat cells (adipocytes) activates a complex network of genetic pathways and molecular signals. One consequence is insulin resistance, when cells become less responsive to insulin's efforts to maintain healthy blood sugar levels. Another outcome is a state of chronic, low-level inflammation throughout the body that triggers blood vessel damage and a raised risk of cancer.

In June, two HSPH research teams published separate findings involving unforeseen control points in the metabolic networks — regulatory mechanisms that might serve as new targets for drugs designed to treat the symptoms of metabolic syndrome.

Dual Role of Molecule in Mice May Open New Avenue to Cholesterol Reduction

Laurie Glimcher, Irene Heinz Given professor of immunology in the Department of Immunology and Infectious Diseases, is senior author of the report published in the June 13, 2008, issue of Science. First author is research scientist Ann Hwee Lee.

The scientists found a molecular switch that prompts the liver to make cholesterol and triglyceride fats when activated by ingestion of a high carbohydrate diet in mice. When excess amounts of cholesterol and fat are carried in the blood for storage in fatty tissue, they raise the risks of heart disease and strokes.

The switch is named XBP1 — and was first discovered by Glimcher 20 years ago in a different context. Subsequently, she and others found that XBP1 functions as a coordinator of the Unfolded Protein Response, (UPR), an emergency response that cells use to survive when they are threatened by the stress of misfolded proteins.

XBP1 also is essential for the fetal liver to develop normally, but its role in the adult liver was unknown. Lee and colleagues devised a way to knock out XBP1 function in normal adult mice, and, to their surprise, found that the rodents were apparently normal, with no sign of liver damage.

What they did observe, however, was a dramatic decrease of cholesterol, triglycerides, and free fatty acids in the XBP1-knockout mice compared with normal controls. Moreover, the lack of XBP1 almost entirely eliminated the "bad" LDL cholesterol in the bloodstream. Concerned that the triglycerides might be accumulating in the liver instead — a condition in humans called "fatty liver" — the researchers found this was not the case, indicating that the manufacture of triglycerides in the liver was shut down.

The Glimcher team concluded that XBP1 has a distinct role in generating lipids in the liver when stimulated by a high-carbohydrate diet and that this role is not connected in any way with its function as a regulator of the unfolded protein response. Because XBP1 acts in such a selective way on the liver's lipid-making mechanism, the researchers are eager to determine whether drugs targeted to the molecule have a future in treating individuals with high blood levels of triglycerides and cholesterol.

Such compounds would work differently from statins, drugs widely used to lower bad cholesterol. "We don't yet know whether blocking the XBP1 pathway will be better than the statins, which are very good drugs but have side effects like all drugs do," Glimcher said. "But it is a different pathway."

Natural Inflammation-Fighting Mechanism

Chih-Hao Lee, the senior author of the second paper, published June 3, 2008, in Cell Metabolism, is assistant professor of genetics and complex diseases. The first author, Kihwa Kang, is a research fellow in that department.

The anti-inflammatory signaling pathway they identified serves as a natural counterbalance to a parallel signaling chain that promotes inflammation and can lead to insulin resistance — a prelude to diabetes — and other ailments such as heart disease, said the authors. In lean people, the dueling pathways maintain a healthy balance — but only up to a point. "Overt obesity eventually overwhelms the protective effect of this pathway and flips it into the pro-inflammatory pathway," said Lee.

The way this happens is that adipocytes, when they become enlarged with fat, produce pro-inflammatory stimuli, such as free fatty acids. These stimuli induce the activation of immune cells residing within fat tissues, called M1 macrophages, which in turn release pro-inflammatory cytokines, such as TNFalpha, that cause fat tissue dysfunction and insulin resistance. Cytokines are messenger chemicals that enable communication between immune cells but could also be produced by fat cells.

Another type of macrophage, known as M2, has the opposite effect, quelling the inflammatory response to free fatty acids. The process that induces M2 macrophages is known as "alternative activation." Until now, the mechanisms controlling M2 macrophage activation within fat tissues had been unclear, as was whether adipocytes controlled this process.

The researchers found that the key to the activation switch is a molecule known as PPAR-d within macrophages. PPAR-d is a "nuclear receptor" that receives the cytokine signals and turns on a cascade of genes and proteins that results in M2 macrophage activation.

Experiments showed that mice in which the PPAR-D function was knocked out could not switch on the M2 macrophage pathway. When fed a high-fat diet, those mice became obese and developed insulin resistance, confirming the key role of PPAR-d as a switch governing the two pathways.

Surprisingly, the researchers looked in liver cells and found they contain the switching mechanism.  Mice lacking PPAR-d developed the condition known as "fatty liver," which also occurs in humans who have metabolic disruption.

Lee is hopeful that drugs targeting PPAR-d may be useful in treating insulin resistance and diabetes. And now that the same mechanism has been identified in liver cells, the same strategy might lead to novel therapies for fatty liver. Finally, the link between obesity, inflammation, and atherosclerosis suggests that PPAR-d-targeted drugs could have potential in preventing heart disease as well.

Gökhan Hotamisligil, chair of the Department of Genetics and Complex Diseases and pioneer in the study of metabolic disease, commented: "This is a fascinating insight into the inflammatory component of metabolic disease. The big question here is how much these immune cells contribute to the overall inflammation and metabolic deterioration. That is, are they of sufficient magnitude to serve as a good therapeutic target?"

—Richard Saltus. Image from CDC/Dr. Edwin P. Ewing, Jr.