Researchers Discover Switch for Controlling Fat Cells
Aug 5, 2013 - 10:04:07 AM
The finding could open the door to developing new therapies for controlling obesity and the myriad diseases and conditions associated with it, such as type-2 diabetes, heart disease and certain cancers.
The switch is the vitamin D receptor, or VDR, a protein that binds with the hormone vitamin D. It's thought that the primary function of these combined molecules is to maintain adequate calcium levels in the body. (Evidence of other functions also has recently emerged.)
In addition, the VDR turns out to exert critical control in determining whether fat cells become the brown, energy-burning variety or the white, energy-storing type, said Brian Feldman, MD, PhD, an assistant professor of pediatric endocrinology who also sees patients at Lucile Packard Children's Hospital.
Feldman is the senior author of the study, published online Aug. 1 in Molecular Endocrinology. Peter Malloy, PhD, a senior research scientist at Stanford, is the lead author.
"When we first made this discovery, we were curious about whether the amount of vitamin D that people were taking might be decreasing how much brown fat they had," said Feldman, who is also a Bechtel Endowed Faculty Scholar. "But so far our data show that this activity of the receptor is independent of vitamin D, so people's ingestion or reserves of vitamin D are unlikely to be affecting this process."
The researchers worked with fibroblast cells isolated from people afflicted with a condition known as hereditary, vitamin D-resistant rickets, which is caused by mutations that eliminate or decrease the activity of the vitamin D receptor. (A fibroblast is a type of cell found in connective tissue.)
When Feldman and Malloy induced the receptor-deficient cells to become fat cells in the lab, far more brown-fat cells were produced than white ones, compared to what was observed in a control group of fibroblasts from healthy volunteers.
Earlier studies in mice showed that when VDR is deleted from the genome, those animals have an increased amount of brown fat. But it has been unclear from the earlier work if this was the result of systemic changes in the animal or specific changes in the precursor cells that eventually become fat cells. This new study shows that the change in the type of fat produced can be regulated independently from the systemic environment. This is also the first time anyone has shown that the effect holds true in human cells.
VDR is known to work by binding to certain small sections of DNA, thereby regulating the expression of particular genes. Uncoupling protein 1, or UCP1, is a protein that is crucial for the production of brown fat. So using fibroblasts, Feldman and Malloy surveyed the human UCP1 gene, searching for sites on the DNA sequence where VDR might bind and then testing for its presence. Through this process, they identified a specific site near the gene for UCP1 where VDR was binding and blocking expression of UCP1. They showed that in the cells from rickets patients, when VDR was not bound to that particular site, UCP1 was expressed.
Because UCP1 is critical to allowing brown fat cells to burn off their energy, blocking production of the protein was enough to tilt the proportion of fat cells towards the inactive, energy-storing white cells.
Feldman said it is uncertain whether VDR actually causes white-fat cells to transform and develop characteristics of brown-fat cells, or if the protein affects cells earlier in the process of becoming a fat cell, causing the determination of brown or white to be made before the cell actually develops into a fat cell.
He and Malloy believe the latter explanation is probably the right one, though they haven't disproved the other possibility. But which is correct doesn't affect the potential for developing new therapies for obesity from their discoveries.
Feldman and Malloy have already begun working on developing a therapy that would use some sort of small molecule to block the VDR from inhibiting the production of the UCP1 protein.
"The goal is to keep the VDR from blocking development of brown fat, but not interfere with the receptor's ability to bind with vitamin D and engage in the other processes it regulates, such as calcium homeostasis," Feldman said. "That's what the utopian therapy would be."
The researchers emphasized that even if the therapy they're trying to develop proves effective, it would likely be years before it could be made available to the public.
They also point out that it will be important to compare the brown fat cells that are generated through this approach in the lab to those that are formed naturally in humans in order to understand whether there are differences.
This research was supported in part by a National Institutes of Health Director's New Innovator Award (grant DP2OD006740) and by the Child Health Research Institute at Stanford.
Information about Stanford's Department of Pediatrics, which also supported the work, is available at http://pediatrics.stanford.edu.
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