Metabolic Regulation and Disease

Exploring Energy Metabolism

Bruce Spiegelman, PhD, acknowledges that his work represents an untraditional area of Cancer Biology, the department in which he is a professor. "When I first came to Dana-Farber, I had a strong focus on cell differentiation, which is part of the cancer problem," he says, "and I used fat cells as a model system." Over time, Spiegelman became interested in the control of energy metabolism. Metabolic disease accounts, at least in part, for the rising incidence of cancer despite improvements in treatment during the last two decades, he explains. Today, a major focus of his laboratory is studying how gene transcription regulates energy homeostasis, which has application to the development of new therapies for obesity, diabetes, cardiovascular and neurodegenerative disorders, as well as cancer.

Primary brown preadipocytes give rise to muscle cells when PRDM16 expression is knocked down. 

A culture of primary brown fat preadipocytes was treated with an siRNA vector targeting PRDM16. In these cultures, long, multinucleated, tube-like cells appeared that were strongly marked by green fl uorescent protein, which was coexpressed from the vector. These GFP-expressing cells were stained with an antibody specifi c for the muscle-specifi c protein, myosin heavy chain, demonstrating that they were skeletal myocytes. These results suggest that brown fat cells and skeletal muscle cells are derived from a common precursor and that PRDM16 restricts skeletal muscle gene expression and development. Staining: GFP (green), myosin heavy chain (red), and nuclei (blue).

In a 2008 paper published in the journal Nature – and lauded by the journal Science as one of the year's top 10 scientific breakthroughs – investigators in the Spiegelman laboratory, including first author Patrick Seale, PhD, completely overturned conventional dogma regarding the origin of brown fat. Previously, scientists believed that white fat cells, which store calories, and brown fat cells, which burn energy, arise from the same progenitor. Instead, says Spiegelman, "Brown fat is derived from muscle precursors, not at all from the white fat cell lineage." Through a series of biochemical and in vivo genetic studies, the Spiegelman group traced the lineage of brown fat cells and discovered that these cells share a common precursor with skeletal muscle cells, and that a protein known as PRDM16 acts as a cell-fate switch between the two. Astonishingly, RNAi knockdown of PRDM16 in brown fat cell precursors of mice induced the development of skeletal muscle cells – a "pretty outrageous result," remarks Spiegelman, who observed the multinuclear, tubular muscle cells under the microscope. If confirmed in future studies in the whole mouse or in humans, this unexpected connection between brown fat and skeletal muscle may present an entirely new approach to the treatment of obesity, says Spiegelman. "That's what we're really excited about."

In studies of ischemia and hypoxia, investigators in his lab also discovered a novel transcriptional pathway of angiogenesis that bypasses – and appears to complement - the canonical pathway known as hypoxia inducible factor (HIF)-1α. Until this finding, it was thought that when a cell experiences a crisis, the HIF-1α pathway stimulates vascular endothelial growth factor (VEGF) to develop new blood vessels to protect the cell from injury. In experiments in cultured muscle cells and in the skeletal muscle of mice, however, investigators found that a lack of nutrients and oxygen induced the transcriptional coactivator PGC-1α to stimulate VEGF (the PGC-1α protein activates transcription factors that regulate energy metabolism). "We discovered a separate regulatory pathway, independent of HIF-1α, which leads to induction of the same growth factors through PGC-1α," explains Spiegelman.

So, why would the cell choose one pathway over the other? "We think the two pathways are complementary," he responds, "and that the HIF-1α pathway depends on the relative oxygen tension in the cell, while the PCG-1α pathway depends on its relative energy charge." Although this research was conducted exclusively in skeletal muscle cells, Spiegelman predicts that PGC-1α is likely to function similarly in other cells. Whether it plays a role in the vascularization of tumor cells has yet to be studied.