Deciphering the Body’s Healthy Message

In part one of a four-part series on the nation’s obesity epidemic, BU Today spotlights the innovative research taking place at BU to better understand and solve this health problem.

Susan K. Fried is neither a farmer nor a chef, but she is captivated by varieties of apples and pears. Fried, director of the Boston Nutrition Obesity Research Center (BNORC), has devoted decades of research to the links between genetically determined body fat distribution and the risk of diabetes, heart disease, and possibly cancer. And all the scientific evidence so far indicates that in terms of health, the pears—people who carry fat in their thighs and gluteal fat depots—have a significant edge over the apples, who carry fat around the middle. So when it comes to the health hazards of obesity, it’s time doctors pay attention to a person’s shape in addition to body weight, says Fried, a School of Medicine professor of medicine in the section of endocrinology, diabetes, and nutrition.

A collaborative research center on the Medical Campus for the last 15 years of its 20-year existence, BNORC includes researchers from Boston Medical Center, Tufts Medical Center, the USDA Human Nutrition Research Center on Aging, the Harvard School of Public Health, and three Harvard hospitals: Massachusetts General, Beth Israel Deaconess Medical Center, and Brigham and Women’s. It is funded by the National Institutes of Health. Through its core services, the center supports the research of numerous scientists, including adipocyte biology, epidemiology and genetics, transgenic mice, and clinical and community studies.

Abdominal obesity is easily identified, but often ignored as a major risk factor for diabetes, heart disease, and possibly cancer, Fried says. And ample thighs and gluteal fat depots are, well, underappreciated. “Women may not like having fat thighs, but if you want to be extremely metabolically healthy it’s the best kind of fat to have,” she says. “We know from a lot of clinical studies and big population studies of both men and women that those who put most of their fat below their waists, in their hips and thighs, tend not to get diseases associated with obesity, like diabetes or heart disease, and maybe also cancer.”

While they are not all obese, of course, about half of all women and most men are apple-shaped, she says, and to understand how important fat distribution turns out to be, we need to grasp that, far from being an inactive reservoir for storing excess calories, adipose (or fat) tissue—is physiologically complex, specialized, even elegant. “Fat from different regions of the body is metabolically different,” says Fried, who compares the diversity of fat tissue to the different types of muscle fibers. Fat is an organ capable of communicating with the brain and other organs, including the liver, muscle, and bone. Fried hopes that her research will decipher the different messages sent to the brain by different types of fat, and that eventually, the more healthful directives from thigh fat can be exploited to moderate the metabolic risks associated with belly fat.

Revolution in obesity research

The realization that fat is metabolically active, like other organs, came in 1994, with the discovery of the fat-producing hormone leptin by Jeffrey Friedman, a scientist at Rockefeller University. “They studied two kinds of mice; we knew they looked really similar and they were both obese,” says Fried. “There was this hypothesis about how these mice came to be obese, but nobody knew for years and years and years why. So Jeff Friedman used a genetic approach to discover what ‘the obese gene’ encoded for. Before that, we all argued, ‘It must be something made in the pancreas,’ ‘It must be something made in the brain,’ ‘It must be something made in muscle.’ All that turned out to be wrong; it turned out to be something made out of fat. And that made adipose tissue an endocrine organ. Who would have figured? Believe me, no one figured.”

The discovery of leptin, which modulates food intake, energy expenditure, and body weight maintenance, ignited a revolution in adipose tissue and obesity research, because, as Fried puts it, “We now know that fat cells produce many other hormones that talk to all other organs, the brain, the liver, the muscle.” In studies of mice, those without leptin are morbidly obese and don’t reproduce. And the study of the leptin gene introduced the notion that obesity is far more complex than being the result of overeating. “If we tweak the brain, we can affect fat metabolism at least in an animal, and if you squirt a little leptin into the brain you can affect fat metabolism,” says Fried. “I like to say, ‘Fat rules,’ and I’m not exaggerating too far, although I do realize the brain is important.”

But if fat behaves like an organ, why is it that people with exactly the same amount of body fat have different metabolic risks of obesity depending on where their fat is?

What’s known is that abdominal fat is responsible for the high rates of lipolysis, or fat release, in obesity, says Fried. This can interfere with sugar metabolism and cause inflammation in many body tissues, as well as increase the risk for diabetes and heart disease. Buttock and thigh fat, in contrast, are very efficient at storing fatty acids rather than releasing them, which stresses the body.

Is thigh fat somehow metabolically protective? Fried and her colleagues are edging closer to an answer with studies of the genes that were “turned on” in different fat depots. “First we did a study where we took fat from the belly and the buttock (gluteal) subcutaneous fat, just under the skin, in men and women, lean and obese,” says Fried. “And we looked at every single gene and found about 400 genes that were different in women’s thigh fat and belly fat, and about half that many in male thigh fat versus belly fat.” Not only did the results reflect a major difference between fat in the two regions, but Fried and her team identified some of those key genes, a study that was recently published in the Journal of Clinical Endocrinology & Metabolism.

The researchers also did studies showing that when grown in cell culture in a dish, the two types of fat “remember where they came from,” says Fried. Even “when we grow them in a dish, they retain some of the differences in the specific genes expressed in one deposit compared to the other.”

The next step, she says, is to figure out why. One possibility “is that all the genes that are expressed are different” in response to the environment within each type of fat. Perhaps thigh fat and belly fat have a different kind of blood flow, or a different “extracellular glue holding the tissues together, so they are as different as a liver to a kidney,” she says. “What shuts off some genes early in development that make a thigh fat cell a thigh fat cell or an arm fat cell an arm fat cell?”

The best scenario, says Fried, is to discover a new hormone made by thigh and gluteal fat, and to learn what message that fat is sending to different parts of the body, because that currently mysterious message appears to help the rest of the body stay healthy. “That,” Fried says, “is the pipe dream.”

Next, in part two of our series, “Solving the Childhood Obesity Puzzle.” Read the entire series here.