Key signal in mice that tells stem cells to commit to becoming fat cells

In the June 21 issue of the Proceedings of the National Academy of Sciences, Johns Hopkins researchers report finding a key signal in mice that tells stem cells to commit to becoming fat cells.

The Hopkins team discovered that adding a single protein, dubbed BMP4, induced mouse stem cells to become fat cells. A very similar signal is likely to be involved in humans, too, say the scientists.

Fat cells, or adipocytes, store the body's excess energy both by increasing their size by "stuffing" themselves full of fat, and by increasing their number. Stem cells are cellular "reserves" that hang around until told to change into another, more specialized type of cell.

The stem cells that the Hopkins team studied have the ability to become fat, muscle, bone or cartilage, but how they commit to these fates is pretty murky. For the past 15 years, researchers have known about signals -- those for muscle and bone -- that direct this type of stem cell to a particular fate.

"Apart from the muscle- and bone-inducing signals, not much is known about the initial switch from stem cell to labeled 'pre-fat' cell," says Daniel Lane, Ph.D., professor of biological chemistry. "BMP4 is the first proven fat-cell producing signal for these stem cells."

To see if BMP4 could direct stem cells to become fat in culture dishes, the researchers treated cells with this suspected, but not yet proven fat-commitment protein. Qi-Qun Tang, M.D., Ph.D., assistant professor of pediatrics and biological chemistry, and postdoctoral fellow Tamara Otto, Ph.D., discovered that these treated stem cells, when pushed a little more, uniformly became fat cells. Stem cells not exposed to BMP4 didn't become fat cells when pushed with a"cocktail" of differentiation-inducers that the researchers had previously shown makes "pre-fat" cells convert into fat cells.

Furthermore, BMP4-treated stem cells implanted under the skin of mice developed into fat tissue that was indistinguishable from the animals' natural fat tissue. "Once we know the detailed mechanism of BMP4-signaling in fat cells, we can create drugs that interfere with the generation of stem cells, and we may be able to create drugs that interfere with the generation of fat cells in both the cell culture and live animal model systems," says Tang.

BMP4, which stands for bone morphogenic protein 4, is a protein that turns on or off genes involved in cell function and growth. Identifying which genes are affected by BMP4 is likely to hold more clues to how stem cells commit to a more specific cell fate, say the researchers.

"With our new experimental system, we were able to demonstrate that one protein, BMP4, can commit stem cells in both culture dishes and live animals," says Lane. "Now we have a way to look for all of the players that cause stem cells to commit to become fat cells."

Historically, it was thought that animals, including humans, had a fixed number of fat cells deposited at birth and that the cells just "swelled" as weight increased. Within the past 10 years, researchers have discovered that stem cells lie in wait within the fat deposits. Just a few years ago, Tang, first author on this paper, discovered that "pre-fat" cells -- a step in between stem cells and fat cells -- divide twice before becoming full-fledged fat cells.

Similarly, in their current study, Tang and Otto observed that BMP4-treated stem cells also undergo these divisions when induced to differentiate. This verified their pre-fat cell character. "Remarkably, we can get essentially 100 percent of these committed cells to become fat cells," says Tang.

The scientists suspect that a number of other proteins will also be involved in the control of fat-cell commitment. In the future, they and other colleagues will use these cells and BMP4 to look at differences of committed and non-committed stem cells to pinpoint other key proteins (and genes).

These mouse "master-controller" proteins will likely have human counterparts, since both species have very similar proteins and developmental pathways. "There are likely to be many genes involved in commitment to fat-cell development," says Lane. "The key ones will likely be turned on early in the game, and hopefully we'll be able to detect them."

The research was supported by the National Institute of Diabetes & Digestive & Kidney Disease. Authors on the paper are Johns Hopkins researchers Tang, Otto and Lane, from the departments of Biological Chemistry and Pediatrics.