Greater ability to study how fat cells develop will aid basic studies and discovery of drugs for obesity and diabetes
BOSTON – (June 16, 2015) – Since the 2009 discovery that energy-burning brown fat can be active in adults, research has raced ahead to understand this tissue and exploit it to treat the epidemic of obesity. Active brown fat also may assist in directly easing the burden of diabetes and related metabolic diseases by lowering the levels of glucose and fatty acids in the bloodstream. But progress in studying human brown fat often has been slowed by difficulties in obtaining and studying samples of the human cells that develop into brown fat.
Co-author of the paper Matthew Lynes, Ph.D., Research Fellow at Joslin, with Yu-Hua Tseng, Ph.D., Investigator in the Section on Integrative Physiology and Metabolism at Joslin, and lead author of the paper Ruidan Xue, Ph.D., Research Student at Joslin.
Now, however, a team of researchers led by Yu-Hua Tseng, Ph.D., Investigator in the Section on Integrative Physiology and Metabolism at Joslin Diabetes Center and an Associate Professor of Medicine at Harvard Medical School, has created cell lines of human brown and white fat precursor cells that will help investigators to pick apart the factors that drive the development and activity of each type of cell.
"We can take human brown fat precursor cells, grow them in Petri dishes and then culture them to become energy-dissipating cells," says Dr. Tseng. "This cellular system provides a very important and exciting tool for understanding the biology of human brown fat tissue. It also offers a really nice system for drug screening."
The cell lines will allow scientists to study gene expression in precursor brown fat and white fat cells, and in the mature fat cells these cells create. Such analyses will improve our understanding of how brown fat cells develop and are regulated in the body—and, potentially, how to transform the precursors of white fat cells into brown fat cells instead, says Dr. Tseng.
As the Joslin team reports in the journal Nature Medicine, the work began with taking samples of both brown and white precursor cells from four human subjects and genetically modifying these cells to "immortalize" them for long life in a Petri dish. The cells also were given a fluorescent marker to show activation of the UCP1 gene, the best known molecular indicator of how much energy a fat cell burns. The researchers then could induce the precursor cells to become mature fat cells and characterize the results.
After analyzing gene expression signatures in the precursor cells, the investigators demonstrated that they could reliably predict UCP1 expression in the resulting mature cells. They took an extra step to verify such predictions by examining the roles of two genes important in brown fat regulation known as PREX1 and EDRNB. When they used a genomic editing technique known as CRISPR/Cas9 to knock down the expression of these genes in precursor cells, the expression of UCP1 did indeed drop in the subsequent mature cells.
The scientists also found that a protein known as CD29 acts as a cell-surface marker for precursor fat cells that can generate mature cells with high energy potential, as shown by their UCP1 expression.
Detection of this CD29 marker eventually may help in selecting white fat precursor cells that can be transformed for obesity treatments, Dr. Tseng comments.
Using white fat tissue from liposuction or weight-loss surgery, "we might purify a population of these progenitor cells from an obese individual expressing C29 with high potential to become energy-dissipating cells," she explains. "We could purify these cells, expand them in vitro, turn them into brown fat cells and then put them back into the patient, and the patient wouldn't have to worry about immune rejection of these cells."
Previous studies had highlighted differences in brown fat metabolism between individuals and between various brown fat depots in an individual. Unsurprisingly, the latest research highlights this heterogeneity.
In one example, Dr. Tseng's group previously had shown that exposing precursor white fat cells to a protein known as BMP7 helps to spur the creation of brown fat cells. In analyses of the cell lines, precursor white fat cells from two subjects responded strongly to BMP7 but such cells from the other two subjects did not.
Despite such variations across individuals, Dr. Tseng emphasizes that her team's work underlines the high promise of energy-burning brown fat. "Our data eventually will help us to develop the best treatment for each patient," she says.
Ruidan Xue was lead author on the paper. Joslin co-authors included Matthew Lynes, Aaron Cypess, Jonathan Dreyfuss, Farnaz Shamsi, Laurie Goodyear, Tian Lian Huang, Tim Schulz, Hirokazu Takahashi, Kristy Townsend, Lauren Weiner and Hongbin Zhang. Other contributors included Andrew White of Beth Israel Deaconess Medical Center, Yiming Li of Fudan University, and Maureen Lynes and Lee Rubin of Harvard University. The work was funded by the National Institutes of Health, Chugai Pharmaceutical, the American Diabetes Association and the Harvard Stem Cell Institute.