Momentous discoveries about metabolism
“It’s all about timing,” says Dr. Gregory Steinberg, Professor, Division of Endocrinology & Metabolism, Michael G. DeGroote School of Medicine, McMaster University.
“Research is a very competitive field,” he explains. “We’ve been fortunate to get some breaks and come to conclusions just ahead of others.”
Of course, timing isn’t the only factor leading to a successful career in the field of metabolic research. In 2017, Steinberg won the American Diabetes Association (ADA) Outstanding Scientific Achievement Award for “particular independence of thought and originality, significance of discovery and impact”. He is the first scientist from a Canadian university to do so. The international award is given annually to a mid-career scientist under 50 years of age.
And, he is the first recipient of the Canadian Institutes for Health Research (CIHR) Gold Leaf Prize for Outstanding Achievements by an Early Career Investigator.
Steinberg’s work to date has significantly shaped the world’s understanding of how lipid metabolism, insulin sensitivity and energy sensing interact and, when dysregulated, contribute to type II diabetes.
His work focuses on how nutrition, therapeutics and exercise both prevent and treat type II diabetes and cardiovascular disease. In this regard he has discovered that fat metabolism and inflammation in obesity are linked and contribute to the development of insulin resistance.
Discoveries at his McMaster laboratory have shown how metformin (the leading medication for treating type II diabetes) and exercise lower blood sugar and have found new ways to promote calorie burning. He and his coworkers are studying the role of brown fat in energy metabolism, and they are working on ways to translate these findings into new therapies.
Steinberg is also the co-director of the Metabolism and Childhood Obesity Research program at McMaster, and holds a Canada Research Chair and the J. Bruce Duncan Chair in metabolic diseases.
What sparked his interest in metabolism?
In high school, Steinberg, a contemporary of Olympic Gold medallist Simon Whitfield, competed on the junior national triathlon team. “We used to race against each other all the time,” he recalls. In university, he competed in Olympic swimming trials in 1996 and 2000.
“That’s why I was so interested in studying metabolism,” he says. “I wanted to understand what was happening in order to improve how my muscles used energy. I wanted to know how to train and perform better athletically.”
Steinberg studied human kinetics at the University of Guelph, earning his PhD in 2002. He learned how the body metabolizes different fuel sources, e.g., carbohydrate, fat and protein. “For example,” he says, “if you burn more of one, you’re going to burn less of the other.”
His research, conducted in Professor David Dyck’s laboratory, studied how the hormone leptin regulated metabolism in muscle.
His grandmother, who suffered from diabetes, turned his thoughts in another direction. “Her stroke influenced me to think about how I could apply my understanding of exercise to treating diabetes.”
Discoveries down under
He traveled to Australia to work with Professor Bruce E. Kemp, a brilliant biochemist at the University of Melbourne. During postdoctoral research, Steinberg studied protein biochemistry and molecular biology. The knowledge helped him to search for links between exercise and metabolism at the molecular level.
Work in the lab focused on AMP-activated protein kinase (AMPK), now known to be a metabolic sensor that regulates the use of cellular energy. Kemp’s group was the first to clone this enzyme and, at the time, one of few research labs to study it.
They examined the role of AMPK in skeletal muscle, where it contributes to motion and fuel use. Because glucose uptake is impaired in diabetes, “it was a natural thing to look at in that context,” says Steinberg.
“Everyone knew that exercise was good for you, but we didn’t really have an explanation why.”
The discovery that AMPK was “switched on” with exercise changed everything. “All of a sudden, we had a molecular clue of the potential ways in which exercise could mediate beneficial health effects.”
The discovery stimulated research worldwide. It also led Steinberg to ask questions about whether AMPK was lower in muscle of people with obesity and diabetes and could be regulated by inflammatory pathways and hormones.
In 2007, Steinberg became Head of the Metabolism Unit at St. Vincent’s Institute for Medical Research in Melbourne. At age 31, he became a Senior Fellow of the National Health and Medical Research Council of Australia.
Forging ahead in Canada
Opportunity knocked in 2008, and Steinberg returned to Canada to set up a new research program at McMaster University. The Canadian Foundation for Innovation (CFI), Canadian Institutes of Health Research (CIHR), Diabetes Canada and the Natural Science and Engineering Research Council (NSERC) currently fund his research.
His philosophy is simple. “We always start with physiology and the clinical significance of findings then work backwards to try to understand the molecular mechanisms,” he says.
Steinberg’s laboratory has studied AMPK in many different contexts. They include muscle studies, where he showed that a lack of the protein generated couch-potato mice. He then worked on immune cells and the liver, showing AMPK was critical for inhibiting inflammation and lipid synthesis.
Based on this work, he believes that the enzyme may have implications for treating non-alcoholic fatty liver disease, now at epidemic proportions in North America.
More recently, he has become intrigued by the regulation of brown fat, which helps to maintain body temperature in both rodents and humans. “Turning on brown fat may be beneficial for treating diabetes and obesity, because it can utilize a large number of calories very quickly,” he explains.
Steinberg and his coworkers have revealed that serotonin, a hormone produced not only in the brain but in the digestive tract, inhibits the metabolic activity of brown adipose tissue.
“Our discovery that serotonin not only affects caloric intake but also energy expenditure, how we use calories in the body, and how brown fat uses calories may turn out to be very important.”
He believes that, in the future, learning how to inhibit peripheral serotonin synthesis or signaling in brown fat may prove effective in reversing obesity and help to lower blood sugar levels in people with type II diabetes.
With obesity, serotonin levels rise, inhibiting brown fat activity and slowing metabolism. In his laboratory, studies have shown that mice with low circulating serotonin levels don’t develop diabetes, obesity or fatty liver disease.
This finding may have important implications to explain why diets stop working and weight rebounds. When you consume fewer calories over time, he explains, your energy expenditure drops. It means that you need to reduce caloric intake further or exercise more just to maintain weight loss.
People tend to think that dieters who regain weight are just giving into temptation, but that’s not so, he says.
“Why this happens is hardwired into our physiology.”