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Brown fat breakthrough

Human cell models accelerate research into brown fat

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

A team of researchers led by Dr Yu-Hua Tseng, 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. The paper, Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes is published in Nature Medicine.

"We can take human brown fat precursor cells, grow them in Petri dishes and then culture them to become energy-dissipating cells," said 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, explained Tseng.

The researchers took 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 characterise the results.

After analysing 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, added Tseng.

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, 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, Tseng emphasises 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 concluded.

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