There are many ways to die, but most people’s last breath will come when festering plaque in a clogged artery ruptures and triggers a heart attack. Scientists suspect obesity and its molecular sidekick inflammation to be key villains in this scenario and in five of the other six leading causes of death in this country, including stroke, cancer, and type 2 diabetes.
A full amphitheater in the Tosteson Medical Education Center testified to the widespread interest in obesity and inflammation, the theme of this year’s Postgraduate Nutrition Symposium, March 21 and 22. Researchers and clinicians from the Harvard medical and public health community and elsewhere provided a glimpse into the state of the science and its implications.
“Obesity sets the groundwork for a variety of additional health problems,” said Gokhan Hotamisligil, the James Stevens Simmons professor of genetics and metabolism at HSPH, in the opening keynote. “Research into the interactions between the metabolic pathways and inflammatory responses in the body is gaining rapid momentum as we discover key mechanistic players for seemingly wide and unrelated clusters of problems.”
The connections are complicated and can be unpredictable and sometimes contradictory, but this relatively new way of framing research questions already has resulted in unexpected biological insights and potential new therapies.
Fifteen years ago, as a postdoctoral fellow in the Dana–Farber Cancer Institute lab of Bruce Spiegelman, Hotamisligil showed that fat cells of obese rodents released tumor necrosis factor-alpha (TNF-alpha) and that this inflammatory cytokine increased obesity-related insulin resistance in both fat and muscle. Fat used to be regarded as a passive storehouse of extra energy. Scientists now consider fat—especially the visceral kind in the abdomen—an endocrine organ engaged in active molecular crosstalk with other tissues and organs.
Too much fat heats up the conversation in ways that interfere with normal metabolism. A cacophony of metabolic signals, in turn, can incite inflammation. Hotamisligil and others have identified central mechanisms that set the stage for inflammation. Surprisingly, his group has recently discovered, fat cells may have a way to distinguish nutrients from pathogens and control unwarranted inflammatory responses. But in obesity, the system goes awry.
The new paradigm needs to be extended, said Paresh Dandona, professor of medicine at the State University of New York at Buffalo, who studies the markers of metabolic and inflammatory stress in people. “We think of obesity as something arising through genes and environment, part of which is excess macronutrient intake,” Dandona said. “The building blocks come from actual individual acts of macronutrient intake.” Different foods have an immediate impact, he and his colleagues have found, such as orange juice (anti-inflammatory), red wine (neutral), and cream (pro-inflammatory).
Conversely, studies of people and populations implicate the same molecular mechanisms behind healthy lifestyle changes, which so far appear to be more powerful than medicine. Many indicators of oxidative stress and inflammation drop within a week of putting obese people on a diet, Dandona said.
The higher risk posed by extra abdominal fat is better captured in waist measurements than in the body mass index, said Eric Rimm, HSPH associate professor of epidemiology and nutrition, whose group studies the importance of diet and lifestyle on obesity and molecular mediators of disease.
“Diet and lifestyle factors predict fat distribution, obesity-related inflammatory markers, and chronic disease incidence,” Rimm said. “Before we get to treatment, I hope we can think about prevention.”
Basic science findings at Joslin Diabetes Center have already led to a clinical trial of an anti-inflammatory agent for treating type 2 diabetes. Six years ago, Steven Shoelson, HMS professor of medicine at Joslin, reported that very high doses of aspirin worked through a key molecular pathway to improve insulin–glucose tolerance and insulin sensitivity and lowered blood lipid levels in rodents.
The paper set the stage for a multicenter clinical trial to test a stomach-saving formulation called salsalate, said Joslin colleague Allison Goldfine, an HMS assistant professor of medicine. The trial began enrolling people with type 2 diabetes in January. A therapeutically effective dose appears to be very close to the amount that causes ringing in the ears, so the protocol allows participants to adjust down to the maximally tolerated dose.
Immune Cells on the Scene
Macrophages are coming under scrutiny for their role in this mix of disorders as cellular mediators of insulin resistance. In obesity, fat cells recruit these immune-cell henchmen. Somehow, fat and macrophages work together to increase insulin resistance, said Haiyan Xu, assistant professor of medicine at Brown Medical School.
“We don’t know how macrophages and adipocytes interact, but that’s when inflammation and insulin resistance occur,” said Andrew Greenberg, director of the Obesity and Metabolism Laboratory at Tufts University. Macrophage infestation seems to correlate with adipocyte death, he said, as he showed slides of macrophages in fat. They fused to form multinuclear giant cells in “crownlike” structures that engulfed atrophied adipocytes.
In fat, macrophages switch their phenotype from burning glucose for energy to oxidizing free fatty acids, said Chih-Hao Lee, HSPH assistant professor of genetics and complex diseases. In contrast to the classic acute pro-inflammatory phenotypes, the transformed macrophages in fat secrete altered combinations of low-grade inflammatory molecules. A fatty acid–binding receptor on macrophages called PPAR-delta seems to be the gatekeeper sustaining the macrophages in an anti-inflammatory stage, Lee said.
Certain types of free fatty acids, byproducts of dietary fat, also activate a membrane molecule, toll-like receptor 4 (Tlr4), to turn on production of the interleukin-6 inflammatory cytokines, said Jeffrey Flier, the George C. Reisman professor of medicine at HMS and Beth Israel Deaconess Medical Center. Toll-like receptors are key molecules that help alert the immune system to the presence of microbial infections. “Our hypothesis is that Tlr4 is a previously unappreciated link between innate immunity and metabolic function,” Flier said.
The fattening of America can be thought of as a scourge of inflammation that contributes to the rising type 2 diabetes and other health problems, suggested speakers at the 2007 Postgraduate Nutrition Symposium. Adapted from CDC.
Most people these days have detectable atherosclerosis beginning in the preteen years. The danger comes from those plaques with necrotic cores composed of a macrophage graveyard, said Ira Tabas, the Stock professor of medicine at Columbia University. Macrophage death pathways, possibly from endoplasmic reticulum stress, are upregulated in insulin-resistant states, said Tabas, who, with collaborators at Columbia, conducted some of these studies in mice.
Unfortunately, experimental drugs that block the normal storage form of cholesterol were shown to increase heart disease, particularly in people with obesity and diabetes. It is possible that this adverse effect was due to the buildup of the free form of cholesterol in macrophages, which seems to accelerate macrophage death and hardening of the arteries, he said. The drugs were discontinued.