Heavy hitter takes on good fat, bad fat

Dr. Philipp Scherer
Dr. Philipp Scherer

In the early 1990s, Dr. Philipp Scherer found himself in a scientific race that would change the world’s thinking on fat cells.

The Swiss biochemist, now Director of the Touchstone Center for Diabetes Research at UT Southwestern, arrived in America for postdoctoral training at the Whitehead Institute for Biomedical Research in Cambridge, an affiliate of the Massachusetts Institute of Technology.

His research goal: to find proteins that fat cells might emit to communicate with other parts of the body – something most scientists at the time considered unlikely.

The fat cell
The fat cell

In 1993, Dr. Scherer’s routine screen for DNA sequences turned up a protein circulating in the blood that appeared to come only from fat cells. “That new protein could be interesting, or it could just be one that the fat cell produces without much impact on anything,” he remembers thinking initially. “Nobody believed that the fat cell would release anything of significance. They were boring cells by all accounts – just sacks for storing lipid droplets.”

Soon, though, his work took on a sense of urgency. The researcher picked up rumors that a lab at The Rockefeller University in New York City also had found an interesting protein released by fat cells. “We were afraid it was going to be our protein,” Dr. Scherer says.

The Rockefeller find turned out to be leptin, a hormone that signals the brain to quell hunger, reported in a December 1994 Nature article.

The following year, Dr. Scherer published a report on his protein, now known as the hormone adiponectin, in the Journal of Biological Chemistry. Subsequent research showed adiponectin can increase insulin sensitivity in mice to prevent diabetes and also reduce inflammation.

Fat cells get a makeover

The discovery of these two proteins forever altered the image of the lowly adipocyte, or fat cell – transforming it into an integral part of the endocrine system that signals the brain and other parts of the body to regulate metabolism, hunger, body weight, insulin sensitivity, and inflammatory responses.

“I don’t think there’s another tissue that has gone through more of a revolution in terms of how we view it than adipose has over the past 20 years.”

Dr. Philipp Scherer

The discoveries of adiponectin and leptin, combined with the growing incidence of obesity, Type 2 diabetes, and fatty liver disease, accelerated research into fat cell activity, now a hot field.

“All of a sudden, people said, ‘Oh, my! Maybe we should pay attention to what the fat cell releases. Maybe some of these molecules play important roles.’

“I don’t think there’s another tissue that has gone through more of a revolution in terms of how we view it than adipose has over the past 20 years.” Dr. Scherer says.

The road to lipid research

For Dr. Scherer, focusing on the proteins exiting fat cells was perhaps a natural inclination. He spent his childhood watching trains pull out of stations where his family lived with his stationmaster father.

However, if not for a year spent as a high school exchange student in the U.S., he might have become a linguist rather than a scientist.

In America, Dr. Scherer found Advanced Placement chemistry a little easier than in Switzerland. Also, since he knew his Swiss high school wouldn’t give credit for the American coursework, he could “enjoy the science for the science’s sake,” he recalls.

Dr. Scherer playing basketball
Pickup basketball game between UT Southwestern researchers and cardiologists, with Dr. Scherer in green

Dr. Scherer spent some of his free time playing basketball on the upstate New York school’s team. (He now regularly plays in a Friday pickup game between UT Southwestern researchers and cardiologists.) He also stayed after school to do experiments in the chemistry lab. “You mix two things and they change color, or you make a plastic. It was a treat to go through these courses and just basically for a year be curious and follow whatever your interests were.”

By the time he returned to his picturesque hometown at the foot of the Swiss Alps, the teen who once considered majoring in French planned a career in science instead.

It was the early 1980s, and scientists were manipulating DNA. “That was pretty fascinating,” Dr. Scherer says. The Swiss microbiologist Dr. Werner Arber became a local hero as co-recipient of the 1978 Nobel Prize in Physiology or Medicine for his work using restriction enzymes to break apart and study DNA molecules, Dr. Scherer says.

After high school, Dr. Scherer went to the University of Basel in Switzerland – where Dr. Arber taught – for a master’s degree in biology and a Ph.D. in biochemistry.

After his postdoctoral work at the Whitehead Institute, Dr. Scherer headed to the Albert Einstein College of Medicine as an Assistant Professor, continuing his research on adiponectin and protein trafficking in the fat cell. He joined UT Southwestern in 2007 as Professor of Internal Medicine and Cell Biology.

Adiponectin interest slowly grows

While leptin was all the rage in fat cell research during this time, the response to Dr. Scherer’s adiponectin study was more muted.

“Ours did not create much of a wave. It probably took five years before people started to pay attention to adiponectin. It was a little depressing that no one paid much attention,” he says.

“The basic finding was that you can eat and become obese and still not have diabetes as long as you increase your fat stores in a productive way.”

Dr. Philipp Scherer

His 2001 paper in Nature Medicine finally created adiponectin’s big splash, with a researcher from his lab interviewed on CNN about their work. In this study from his lab, Dr. Scherer showed that an injection of adiponectin into mice could lower the high blood sugar levels associated with Type 2 diabetes. “We gave adiponectin to diabetic mice and their diabetes went away,” Dr. Scherer says.

“If there was an ‘aha’ moment, that would have been it,” he adds. “From that point on, the entire field gained a lot more momentum.”

Other studies followed. A 2004 report in Nature Medicine outlined adiponectin’s effect on energy homeostasis: Injecting mice with adiponectin caused an increase in heat production, as well as weight loss accompanied by a drop in blood glucose and lipid levels.

Wang, Scherer, and Gupta
Wang, Scherer and Gupta J. Lipid Res. 2014. 55: 605-624

His UT Southwestern laboratory showed in a Nature Medicine study in 2012 that high levels of another fat cell protein, mitoNEET, allowed adipocytes in mice to expand and store more lipids without the expected insulin resistance and diabetes – essentially creating a healthy form of obesity. “Using mitoNEET, we managed to generate the world’s fattest mice ever. Despite being fat – rather than having inflammation and diabetes – their fat was happy, productive, and healthy.”

Dr. Scherer’s fattest mouse weighed in at a whopping 4.5 ounces compared with the typical mouse weight of less than 1 ounce.

“The basic finding was that you can eat and become obese and still not have diabetes as long as you increase your fat stores in a productive way,” he says.

Since humans aren’t good at losing weight and keeping it off, this might be a strategy to avoid disease, Dr. Scherer says. “Neither the leptin nor adiponectin discoveries have so far cured diabetes.” 

What’s next?

After almost 25 years, there’s still much to learn. “We really don’t understand leptin. And we still don’t understand adiponectin. We want to learn more about how these components talk to each other and how they act in concert with each other. We’ve been listening to individual instruments. Now we want to hear the whole orchestra play,” says Dr. Scherer, who holds the Gifford O. Touchstone, Jr. and Randolph G. Touchstone Distinguished Chair in Diabetes Research.

Over the years, Dr. Scherer’s research has shown that the subcutaneous fat everyone loves to hate is actually beneficial – and necessary.

His lab also researches the link between obesity and breast cancer, because some early breast cancer cells appear to grow only in the presence of fat. “When you are obese, you are in danger of having many of the different diseases out there,” he points out.

Dr. Scherer also wants to see if increasing blood vessels within fat tissue could eliminate the inflammation that results when fat cells outgrow their blood supply.

And he is still looking for a chemical that could be put into a pill to boost adiponectin and increase insulin sensitivity to ward off diabetes.

Over the years, Dr. Scherer’s research has shown that the subcutaneous fat everyone loves to hate is actually beneficial – and necessary. Without this energy sink for excess calories, lipids would move into organs such as the heart and liver, creating the health problems associated with obesity – when the fat builds up in those organs, to their detriment – Dr. Scherer says.

About 25 percent of the world’s population now has nonalcoholic fatty liver disease (NAFLD) (the kind affecting people who don’t drink excessively). The disease can lead to liver damage and cirrhosis or even liver cancer, according to the National Institutes of Health.

Honors in lipid research

“We’re trying to understand what makes healthy fat healthy and what makes unhealthy fat unhealthy.”

Dr. Philipp Scherer

The world of diabetes research has showered Dr. Scherer with its top prizes: the Manpei Suzuki International Prize for Diabetes Research (2018); the EASD-Novo Nordisk Foundation Diabetes Prize for Excellence (2017); and the Banting Medal for Scientific Achievement from the American Diabetes Association (2015).

Despite the acclaim, Dr. Scherer keeps busy exploring fat tissue. He’s still looking over his shoulder, churning out advances in fat cell research along the way.

“You don’t want to be the guy who discovered adiponectin and really hasn’t done much of anything else since then,” he says. “We’re trying to understand what makes healthy fat healthy and what makes unhealthy fat unhealthy.”