Architects of Metabolism
Andreas Stahl's campus collaborations in fighting obesity with fat
If 17 seasons of The Biggest Loser have taught us anything, it’s that keeping the pounds off can be harder than losing them in the first place. A long-term National Institutes of Health (NIH) study of 14 of the reality show’s eighth-season contestants, for example, found that in the six years following that competition, all but one regained weight—and four ended up heavier than before the competition. Even more interesting: All but two contestants exhibited slower metabolisms than they had before the show, burning hundreds fewer calories per day than a typical man or woman of their size.
More than one-third of adults in the United States and 10 percent of people worldwide are considered to be obese. But it’s the potential complications of obesity—including type 2 diabetes, heart disease and stroke, fatty liver disease, and some cancers—that most concern Professor Andreas Stahl. “Combating obesity is a huge problem, and in particular the chronic diseases associated with it have placed a large strain on our health care system,” says Stahl, who is chair of the Department of Nutritional Sciences and Toxicology. “These diseases are very expensive to treat, and there can be very drastic consequences.”
The NIH findings lend credence to Stahl’s belief that for many obese individuals, diet and exercise alone aren’t enough—and may in fact be quite unlikely to work. “I think there need to be behavioral interventions in parallel with other approaches,” says Stahl. Approaches, that is, like using tissue engineering and “metabolic therapy” to fire up one of the body’s most effective calorie-burning engines: brown fat.
Up until eight years ago, scientists thought that brown fat existed only in babies, where it plays an important role in generating lifesaving heat. Now we know that adults can have it too, and through cutting-edge research and collaborations with colleagues in the colleges of chemistry and engineering, Stahl is working hard to harness its power in the fight against obesity. His goal: to develop a safe, easy, injectable treatment that can generate new brown fat in a patient’s body and begin to slowly, steadily burn off calories.
In search of the metabolic “sink”
When we talk about excess fat in adults, we’re typically referring to “white” fat, present in large quantities even in healthy individuals. It’s essential to our survival in its own way, storing energy and working as an insulator, cushion, and endocrine organ. The problem comes when we consume more calories than we burn and white fat begins to accumulate in places it shouldn’t, like the liver. This can lead to fatty liver disease, which affects roughly 10 percent of children and a quarter of adults nationwide and contributes to diabetes, liver failure, and increased risk of liver cancers.
Bypassing this chain of events would require finding another way of storing or consuming excess fatty acids. “We need a location where we can put it safely,” Stahl says. And that’s what brown fat is: a sort of “metabolic sink” that generates heat while it’s burning calories.
By introducing the proper signal and cellular “environment” into the body, Stahl believes, we can recruit a specific, relatively abundant type of stem cell; instruct it to become brown fat instead of white fat; and proceed to radiate away excess calories as heat.
Sniffing Out Stem Cells
This may sound impossibly futuristic, but in fact more than half the work is already done. Stahl; his colleague Kevin Healy, a professor of bioengineering and materials science; and seven other collaborators, including five more from UC Berkeley, described in a November 2015 research paper their development of a gel-like substance with the right properties to turn stem cells into brown fat cells. The researchers also demonstrated that their subcutaneously injected implant—a mix of stem cells and an in situ–forming hydrogel—accomplished the end goal of reducing weight gain and blood glucose levels in mice.
The next step, of course, is to extend this technology to humans. “It’s a high-priority project, and I think it has a big social need,” Healy says. But developing the technology for real-world use will require another big advance. Instead of extracting white fat from a subject in order to obtain stem cells that will then be reinjected, Stahl envisions introducing an additional chemical signal into the implant that will actively “recruit” the desired stem cells, summoning them from nearby areas to enter the gel-like matrix, where they will convert to brown fat.
“It’s like a dog sniffing out a scent trail and going toward where the scent is the strongest. Cells can do that with chemicals as well,” Stahl explains. “What we’re working on right now is how to attract the stem cells into the matrix and still be able to turn them into brown fat after they have arrived.”
Tracking copper with bioluminescence
It’s a pressing question, but far from the only one occupying Stahl’s mind. A recent collaboration with chemistry professor Chris Chang and other Berkeley researchers not only led to an obesity-related breakthrough of its own but also laid the groundwork for more progress on brown fat. First, using a novel technique developed by Chang’s lab to track copper inside a live mouse with the help of firefly-derived bioluminescence, the researchers showed that diet-induced fatty liver disease is associated with copper deficiency in the liver.
“It shows you need copper to fight obesity,” Chang says. “If you don’t have enough copper, you can’t burn fat well. That potentially can lead to fat storage, weight gain, and glucose intolerance.” Building on this work, he and Stahl are now attempting to apply a similar bioluminescent marker to brown fat. “We’re really keen on imaging not only where that type of fat is locally in the body, but how active it is under different situations,” Chang says. Achieving this goal could be a big step in the journey from lab to real world for Stahl’s brown fat implant.
Stahl and his team aren’t the only ones seeking to tap the power of brown fat, but they’re certainly at the forefront, driven by a desire to reduce obesity’s huge burden on our society. “We’re trying to tap into this mechanism,” Stahl says. “We want to change the equation where we reduce white fat by expanding brown fat”—not simply to make people skinnier, like so many reality-show contestants, but to lower glucose levels, blood lipid levels, and the amount of calories in circulation, he says. “Those are the things that lead to detrimental effects.”
Fat on a Chip
Andreas Stahl’s mission to beat obesity has generated important insights into brown fat biology and nutrient imaging. But it doesn’t end there. Another line of research—with bioengineering colleague Kevin Healy—resulted in a breakthrough earlier this year and a powerful new tool for research into fat and metabolism.
Stahl, Healy, and their collaborators fit a biologically active, fully functional sample of human white fat—which accounts for one-fourth of the body weight of a typical healthy adult—onto a silicon chip measuring less than one millimeter squared.
This “fat on a chip” device—more technically known as a “microfluidic system incorporating white adipose tissue”—is designed to play at least two important roles in the lab. By replicating the in vivo (“within the living”) experimental model without the use of test animals, it can serve as a test bed for investigating fat-related diseases such as obesity and type 2 diabetes. It can also act as an efficient and highly accurate screening tool for assessing drug effects on white adipose tissue function.
The device stems from earlier work by Healy on other innovative “organ on a chip” systems. In 2015, his lab developed the “heart on a chip”—around 5,000 heart-tissue cells arranged on a chip, beating with the regularity of a human heart—and more recently it did the same for the liver, though that work has not yet been published.
Together with the fat chip, Healy says, these systems form an ideal “minimal metabolic unit” for researching human disease and evaluating drugs with metabolic activity. “There’s a very interesting interaction between the liver and fat,” he says. “This might allow us to look into things associated with high-fat diets, such as diabetes and other imbalances in the metabolic system.”
What’s more, Stahl says, these systems allow researchers to safely test cells taken from specific individuals, opening up new lines of inquiry into mechanisms behind metabolic effects tied to age, race, and other factors. “Humans are genetically diverse, and often people with different backgrounds and ethnicities have different responses to the same drug,” he says.
Healy and Stahl are already working on brown fat on a chip, another step toward their ultimate goal of assembling a complete “multi-organ microfluidic device” that could reveal wonders about the inner workings of human metabolism on a personalized basis. “We want to create the best ‘miniaturized’ human that we can within these different devices,” Stahl says.