Why we are fat



We all know why Americans are fat, right? We gobble chips and chug 16-ounce sodas and then park our butts in front of the TV. Seems pretty straightforward. But what if that’s not the whole story? Biochemist Barbara Corkey has an idea that turns this conventional wisdom on its head.

What if, asks Corkey, obesity isn’t simply about eating too much and exercising too little? What if there’s something more subtle at work? Maybe it isn’t extra calories that make us fat, she says, but food additives like saccharin and emulsifiers.

“I don’t believe that overeating causes obesity,” says Corkey flatly. “During my lifetime I have seen tremendous differences in food preparation and food packaging….When that novelty is associated with an increase in obesity and diabetes, is it rocket science to ask whether these things are related?”

Corkey’s suspected connection may seem like a stretch, but she is not one to oversimplify science. Corkey is a respected scientist with five decades of metabolism research under her belt. She’s the vice chair of research at the School of Medicine department of medicine, and in November was appointed MED’s Zoltan Kohn Professor in Medicine. She’s the former director of the Obesity Research Center at Boston Medical Center and recent past editor of the medical journal Obesity, and last year she was awarded the Banting Medal for Scientific Achievement Award, the American Diabetes Association’s highest scientific honor and one of the world’s top science awards.

“Barbara is out of the box—completely,” says collaborator Orian Shirihai, a MED associate professor of medicine. “She doesn’t even know what’s in the box. What she does is turn the box upside down and put it onto other scientists’ heads.”

Corkey’s area of expertise is metabolism: she studies how cells, specifically cells involved in diabetes and obesity, communicate. “Metabolic disease has always interested me,” she says. “It’s a system where pathways all interconnect and talk to each other. And so if you push on one button over here, it has consequences everywhere else.”

A key player in her research is the pancreatic beta cell, which produces insulin, a hormone that converts food into energy and stores it as either fat or glucose. In diabetics, the beta cells usually produce too much, too little, or no insulin. The reasons for beta cell breakdown are complicated, and that’s what attracts Corkey.

“Barbara is one of the few people who really understand and integrate metabolism into diabetes research,” says Ronald Kahn, past president of the Joslin Diabetes Center and a professor of medicine at Harvard Medical School. “Metabolism is coming back now, but for the last 30 years it has been a lost science.” Kahn, who calls Corkey “the queen of metabolism,” says that “she helped keep the field alive.”

Fortuitously, it turns out. Diabetes now threatens to become a worldwide epidemic. According to the U.S. Centers for Disease Control and Prevention (CDC), 25.8 million children and adults in the United States—8.3 percent of the population—have the disease, which is the leading cause of kidney failure and blindness among adults. If current trends continue, a third of U.S. adults could have diabetes by 2050. Outside the United States, the numbers are equally grim. According to the World Health Organization (WHO), 346 million people worldwide—5 percent of all humans—have diabetes, and diabetes deaths will likely double by 2030.

Decades ago, when the disease was not well understood, scientists knew that two types of diabetes existed—type 1 and type 2—but they didn’t have a clear picture of the underlying causes. People with type 1 diabetes, which is usually diagnosed in children, cannot produce insulin and must inject it to survive. Scientists thought that type 2 diabetics, who are usually adults and often obese, had a less dramatic deficit: some insulin but not enough. But when scientists came up with a way to measure insulin levels, they found that people with type 2 diabetes actually had too much insulin.

If they had plenty of insulin, what caused the diabetes? The researchers theorized that insulin receptors in the muscle and fat tissue, bombarded by an excess of the hormone, became desensitized and didn’t work as they should. This “insulin resistance” causes the beta cell to crank out more insulin, and sometimes to stop working altogether. By the 1980s, the idea that insulin resistance alone causes type 2 diabetes had solidified into scientific dogma.

There was only one catch: nobody knew which came first, the broken beta cells or the insulin resistance. Corkey was determined to find out. “I think perversely,” she says. “Why is the beta cell secreting more insulin? The glucose isn’t elevated. How can we explain this?” She suspected that the beta cells were partly responsible for triggering diabetes. And she spent the next two decades trying to prove it.

The role of outsider suits her. “I like to be in a comfortable place where we don’t have to compete and rush, and we can do our science in a thoughtful and leisurely manner,” she says. By all accounts Corkey also enjoys the role of scientific gadfly.

“She likes to be provocative,” says Sarah Krawczyk (MED’11), one of Corkey’s postdoctoral students. “Lots of her theories challenge dogma, though they’re always backed up by sound science.” For two decades, while insulin resistance dominated diabetes research in the United States, Corkey stuck stubbornly with the beta cell theory. “I just thought the whole United States was wrong,” she says.

She was right. Scientists now widely accept that a person can’t get type 2 diabetes without malfunctioning beta cells, a paradigm shift largely precipitated by Corkey.

“She just really changed that field and put metabolism into it, and she’s basically regarded as the expert,” says Susan K. Fried, a MED professor of endocrinology, diabetes, and nutrition. The beta cell research, along with similar work on fat cell metabolism, helped Corkey win the 2011 Banting Medal. “She was such a perfect choice,” says Kahn. “She is an excellent scientist with a huge body of work, and she has been such an important catalyst in diabetes research.”