Like good and bad cholesterol, human body fat comes in two varieties: white fat cells, which store excess calories, and brown fat cells, which burn energy to generate body heat. Less well known outside the scientific community, brown fat cells have long been a fascination for National Academy of Sciences member Bruce Spiegelman, a professor of cell biology at Dana–Farber Cancer Institute and Harvard Medical School. Spiegelman’s work on fat metabolism is far-reaching: From finding ways to stimulate brown fat development in the body to unraveling the activity of drugs against diabetes, he has shown how understanding the genetics of fat cell development can pave the way for therapeutic approaches to diabetes and obesity. Spiegelman discusses his findings on fat metabolism with PNAS.
Bruce M. Spiegeiman.
PNAS: Your work has revealed that white fat cells can be converted into brown fat cells. What are the implications of that finding for obesity?
Spiegelman: For a long time, we were hunting for factors that control the identity and function of brown fat cells. Using genomic approaches, we identified a handful of genes that were more highly expressed in brown fat cells than in white fat cells. When one such gene, called PRDM16, was inserted into precursors of white fat cells, the cells adopted characteristics of brown fat cells. When the gene was knocked down or out, the cells lost those brown fat-like characteristics. Because brown fat protects against diabetes and obesity in mammals, boosting it opens avenues to countering those diseases.
PNAS: You have tried to engineer brown fat cells experimentally from other kinds of cells. What did you hope to achieve with those efforts?
Spiegelman: Our efforts to engineer brown fat cells from fibroblasts (skin cells) helped us to understand better the development of brown fat in the body. When we inserted PRDM16 and a gene switch called CEBP-beta, which interacts with PRDM16, into fibroblasts, which normally have none of the traits of fat cells, the cells turned into brown fat cells. These two factors are not the only players involved in the development of brown fat cells, but they are sufficient to turn human skin cells into brown fat cells under laboratory conditions. Engineering brown fat cells with the hope of treating obesity is currently far-fetched, but stimulating this developmental pathway with chemicals has potential implications for treatment. Work on using drugs to modulate brown fat identity and function safely and reliably is underway.
PNAS: In a surprising discovery, you found that tinkering with PRDM16 in brown fat cells could also turn them into muscle cells. How does that work?
Spiegelman: In 2008, my postdoctoral fellow Patrick Seale used RNAi to knock down PRDM16 in primary brown fat precursor cells grown in laboratory dishes. The expectation was that they would turn into white fat cells. But, to our surprise, the cells switched fate and turned into muscle cells. That was probably the most shocking result in my 30 years as a principal investigator. The converse worked as well; we could insert PRDM16 into muscle cells and have them turn into brown fat cells. Contrary to the then-widespread belief that brown and white fat cells shared a common precursor, our work showed that brown fat cells, which share a precursor with muscle, come from a different lineage than white fat cells. Identifying factors responsible for brown fat development can lead to ways to stimulate it.
PNAS: One such factor was the protein PGC-1α that you identified. What does this protein do in cells?
Spiegelman: We discovered PGC-1α, a gene switch that, like PRDM16, endows white fat precursor cells with some of the properties of brown fat cells (the effect is not as pronounced as that obtained with PRDM16). Over the years, we and others have found that PGC-1α might be a master regulator of mitochondrial biogenesis. Then, in 2006, we found that PGC-1α, which is also found in the brain, protects neurons against oxidative stress by turning on genes involved in the detoxification of reactive oxygen species.
PNAS: Does that imply PGC-1α in neurodegenerative diseases?
Spiegelman: Several lines of evidence now point to the protective role played by this protein against neurodegeneration. Loss of PGC-1α leads to major neurodegeneration in a brain region that goes awry in Huntington disease. Other researchers have implicated the protein in protection against Parkinson disease.
PNAS: On a related but different topic, you unearthed a biochemical basis for the function of diabetes drugs like Avandia and Actos. Can you explain your findings?
Spiegelman: In the 1990s, we showed that a protein called PPARγ was the master regulator of fat cell formation. Shortly afterward, a group at GlaxoSmithKline found that the protein was also a receptor for thiazolidinedione drugs like Avandia. Those drugs were developed without knowledge of their molecular targets; for several years, people had assumed that the drugs worked by activating PPARγ. An odd series of experimental observations led us to suspect that despite being classic PPARγ activators, those drugs had a secondary activity responsible for their therapeutic effect against diabetes. We found that these drugs blocked the phosphorylation (a chemical modification that can turn proteins on or off) of PPARγ. The ability of the drugs to block this phosphorylation correlated a lot better with their clinical effect than did their direct, activating effect on PPARγ.
PNAS: But Avandia use is now largely banned in most of Europe and severely restricted in the United States, thanks to side effects, such as heart attacks. Did your studies help understand the drug’s unintended effects?
Spiegelman: Yes, our studies later revealed that the drug’s side effects, such as heart problems, weight gain, and fluid retention, not its therapeutic effects, were likely attributable to its direct, activating effect on PPARγ. We recently reported in Nature that a new series of chemical compounds that block the phosphorylation of PPARγ without directly activating it have antidiabetic activity. That proof of principle, we hope, will open the door for the development of a new class of diabetes drugs with fewer side effects.
PNAS: Given the multifaceted nature of the signaling pathways involved in obesity, do you think a single drug can help counter the disease?
Spiegelman: In principle, yes. It is a question of energy balance. As we continue to develop a more sophisticated understanding of energy metabolism, I believe that it is feasible to develop a single drug that will have an impact on these pathways. That said, although a focus on drug development is essential to our medical arsenal against obesity, education about diet and exercise is equally important.