Dorothy and Daniel Silberberg Associate Professor of Medicine
Department of Medicine, Columbia University
Naomi Berrie Diabetes Center
About ten years ago, a young physician scientist at the Naomi Berrie Diabetes Center, Anthony W. Ferrante, Jr., MD, PhD, found a crucial piece to the puzzle that explained the health problems that stem from obesity. Dr. Ferrante and team determined that adipose tissue becomes a magnet for a type of immune cell called macrophages when a person gains weight. These cells secreted molecules that not only altered the chemical action of insulin, but also caused inflammation throughout the body. The more weight you carry, the more fat you have, the more macrophages accumulate in your fat.
Today, Dr. Ferrante is a bit of an unassuming urban legend in his field. His seminal study on macrophages is now one of the most frequently cited papers written on metabolism. (It also has the distinction of being the most frequently cited original scientific paper in any category over the last two decades at Columbia.) If you can understand the physiology behind macrophages, Dr. Ferrante explains, “you can interfere with the process of obesity.”
A tall slender man himself, he has a spouse with type 1 diabetes and a father with pre-type 2. “I see both sides of the diabetes world up close and personal each day, every day,” said Dr. Ferrante.
Q: How has the focus of your lab changed in the last few years?
A: We now understand that adipose tissue is a complex organ in which immune cells—mostly macrophages— play a pivotal role. These cells communicate with the surrounding fat cells and we believe the rest of the body. We can eavesdrop on the conversation by measuring the proteins they make but don’t fully understand the conversation. Now, we’re trying to figure out what it is they’re saying and doing, to more fully reconstruct the conversation that goes on everyday in our bodies between our immune cells and the rest of our body.
From our eavesdropping and studies, we’ve learned that these immune cells—mostly the macrophages—are not simply bad guys. We actually think they can do more good than harm if given the opportunity. For one thing, they help regulate the trafficking of the fat into and out of adipose tissue, in a process that is much more complex then we ever imagined.
Another recent finding is that immune cells in fat can tell the brain that the fat depot is overstuffed and instruct it to reduce how much is being eaten. We’re very excited by these findings.
Q: How does this manifest in your laboratory?
A: My relatives ask me a similar question. I tell them we can cure obesity in mice. We have genetically modified animals in which we can specifically activate certain pathways in the macrophages. When we do this, obese mice, but not lean ones, lose fat and weight. Now our challenge is to translate that into people; that would be a great thing.
Q: How did you do that in mice?
A: We discovered a receptor, or stress signal, in the macrophages that once activated, leads to weight loss in the obese mice. We’re not sure why, but certain biological factors told the rest of the body not to eat any more food and to expend energy instead. Now we have to be clever enough to activate and characterize these pathways in more detail—and to show that it’s part of a normal physiological response to eating.
Q: So macrophages—that play an important role in obesity—can also help in weight loss?
A: Yes, absolutely. A goal of our research is to help develop a medication that will lead to weight loss in people. My dad who was 220 pounds, lost 20 pounds and was able to stop his cholesterol medication. A little weight loss goes a long way. If we can find a way for people to lose 10% of their body weight, most will be metabolically much healthier.
There have been a half dozen or so weight control medications. All but one have targeted the central nervous system, affecting the mood and/or the heart, and all were taken off the market. We think that activating the immune system may reduce food intake in a way that does not involve mood or the heart.
Click here to support Dr. Ferrante's work at the Naomi Berrie Diabetes Center.