By Terry Taylor

June 6, 2012

By age 34, John had been obese for much of his life. Feeling chronically fatigued, he visited his doctor. John’s tests showed insulin resistance and pre-diabetes. Because of his weight and his family history, John was also at increased risk for heart disease and stroke. John’s doctor told him he had to increase his exercise and eat a better diet, and strongly urged him to lose weight. The doctor also prescribed a new drug intended to treat the insulin resistance and pre-diabetes. Within a month, John’s tests showed improvement.

We are several steps closer to a medical intervention like the one described above, according to recently reported findings of a possible new drug target from Andrew S. Greenberg, M.D., the Dr. Robert C. and Veronica Atkins Professor in Metabolism and Nutrition at Tufts Medical School; Director, Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University; and Associate Professor at the Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University.

Obesity and its many health consequences have become epidemic, not just in the United States but also around the world. One in three Americans today is obese, and deaths directly related to obesity in the United States total approximately 300,000 each year. One important consequence of obesity can be insulin resistance—often the first step on the slippery slope to diabetes.

More than 80 million Americans suffer from insulin resistance. Insulin is a natural hormone made by the pancreas. One of insulin’s jobs is to help cells absorb glucose from the bloodstream. This process not only keeps the supply of fuel to the brain constant—no matter the variable energy needs of the rest of the body—but it also keeps blood sugar levels safe. Too much sugar in the blood, a condition referred to as hyperglycemia, is toxic.

With insulin resistance, more and more insulin must be released to keep cells absorbing glucose and blood sugar levels safe. Excess weight may cause insulin resistance, but one consequence of insulin resistance can be weight gain since the combination of insulin resistance and hyperglycemia may cause a person to feel hungry and eat even more. In other words, fat metabolism is disrupted and obesity becomes self-perpetuating.

Another likely consequence of obesity is inflammation. In fact, research has shown that the process called inflammation is directly related to a greater risk of developing diabetes and other metabolic complications associated with obesity. “Inflammation is actually good for us,” Dr. Greenberg explains, “because it is the way the immune system protects against bacteria and other potential sources of infection. However, obesity activates the immune system, leading to chronic inflammation—and that’s not good.” Indeed, chronic inflammation is associated with diabetes, cardiovascular disease, and cancer.

Dr. Greenberg and his colleagues hypothesized that inflammation occurs because obesity activates a particular protein called tumor progression locus 2 (TPL2), which turns on inflammatory proteins and mediators that promote alterations in blood glucose levels and produce metabolic complications, such as insulin resistance. To test their hypothesis, Dr. Greenberg and his co-investigators used a standard mouse model of obesity and produced mice without the ability to produce TPL2. Armed with preliminary evidence that the absence of TPL2 protected obese mice from insulin resistance and other metabolic consequences, Dr. Greenberg was able to apply successfully for American Recovery and Reinvestment Act (ARRA) funding for a full-scale investigation. The grant allowed him to hire needed research staff, pay for the mice and their upkeep, and fund the complicated testing procedures needed to demonstrate the results.

Andrew S. Greenberg, M.D., the Dr. Robert C. and Veronica Atkins Professor in Metabolism and Nutrition at Tufts Medical School; Director, Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University; and Associate Professor at the Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University. Photo courtesy of Alonso Nichols, Tufts University.

To fully test their hypothesis that obesity-activated TPL2 produces inflammation and its associated health problems, Dr. Greenberg and his co-investigators used the obesity mouse model, including both their TPL2 knockout mice and mice that still produced TPL2. To isolate the effects of knocking out TPL2, some of each type of mice had to be fed a diet high in calories to make them obese and other mice of each type had to eat only regular chow, which did not make them obese.

The mice that were fed regular chow, whether or not they could produce TPL2, showed no ill effects. They did not become obese, did not develop insulin resistance, and did not show chronic inflammation. However, the mice that were fed the high-calorie diet, whether they could or could not produce TPL2, became obese. There the similarity ended. The investigators carefully measured insulin resistance, blood sugar levels, and inflammation. The mice unable to produce TPL2 were indeed protected from ill effects, whereas the obese mice that produced TPL2 showed all of the ill effects.

It is important to note that the obese TPL2 knockout mice in this research did not become less obese, but they were protected against the common adverse outcomes associated with being too heavy. Dr. Greenberg is quick to agree that the general idea of an intervention to treat obesity involves helping people reduce their weight. “Losing weight is very hard,” he says. “However, if we can find an intervention that protects people from many of the health consequences of being obese while they learn to alter their exercise patterns, diet, and other factors, we have made a genuine contribution to their well-being. This research found a mediator that potentially can be targeted to reduce insulin resistance and other negative outcomes associated with obesity.”

Dr. Greenberg and his team also developed cell cultures, using white blood cells isolated from the bone marrow of both types of mice, to allow exploration of the molecular pathway by which TPL2 produces inflammation. Through ARRA funding, the researchers continue to study in detail the molecular mechanisms by which TPL2 alters metabolism. This research has the potential to help identify an agent or agents capable of blocking TPL2 action.

For Dr. Greenberg, the problems he seeks to solve in his research are hardly abstract or faceless. “My mother died of obesity-related diabetes,” he explains. “By doing this research, I hope to identify the causes of and develop therapeutic approaches to counter the obesity epidemic.” The results of this ARRA-funded study suggest that TPL2 is a promising therapeutic target for metabolic complications due to obesity.