Vitamin Receptor Found to Block Fat Browning

The vitamin D receptor (VDR) -- not the vitamin itself -- may inhibit a process that turns adipocytes into "brown" or metabolically active fat, researchers found.

In a series of experiments with human fat cells, VDR inhibited the expression of a key mediator of energy metabolism -- uncoupling protein-1 (UCP1) -- by binding to an area in the promoter proximal region of the gene, Brian Feldman, MD, PhD, and Peter Malloy, PhD, of Stanford University School of Medicine in Stanford, Calif., reported online in Molecular Endocrinology.

Conversely, knocking out the receptor led to expression of UCP1, resulting in a browning of adipocytes, they wrote.

"These data support pursuing the therapeutic strategy of developing factors that specifically target releasing the beige fat expression profile of human cells," they wrote.

As the obesity epidemic grows, more research has focused on the physiology of brown fatand its potential as a treatment target.

Animal studies have shown that altering VDR levels can alter the generation of white andbrown fat, and have also revealed changes in energy expenditure, which led Feldman and Malloy to hypothesize that the receptor could regulate features of 'beiging' these fat cells, or the process of turning white adipocytes into brown ones, in humans as well.

They took skin fibroblasts from patients with hereditary vitamin D resistant rickets (HVDRR), a condition in which VDR directly inhibits the expression of UCP1. They then induced the cells to differentiate into adipocytes, and assessed their expression of UCP1.

Feldman and Malloy observed that VDR inhibited UCP1 expression by occupying a promoter proximal region of the UCP1 gene.

But knocking out the receptor increased UCP1 expression, and resulted in a browning of the adipocytes. In particular, the VDRE4 receptor appeared to be a "critical negative regulatory element controlling UCP1 expression," they wrote.

In further studies, they found that the process appears to occur cell-autonomously and is independent of vitamin D -- in the form of 1,25-dihydroxyvitamin D -- binding to the receptor.

"We found that even pharmacologic doses of calcitriol did not significantly alter UCP1 levels ... compared to the absence of the ligand," they wrote. "These results confirm that the regulation of UCP1 can be uncoupled from other VDR activities and is ligand-independent."

"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," Feldman said in a statement. "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."

Christoph Buettner, MD, PhD, of the Icahn School of Medicine at Mount Sinai Hospital in New York City, who was not involved in the research, also cautioned that vitamin D intake is unlikely to turn bad fat into metabolically active fat.

"This study shows that the vitamin D receptor, not vitamin D, may regulate thermogenesis," Buettner said in an email to MedPage Today. "Thus, vitamin D by itself would not be expected to increase energy expenditure. So do not take vitamin D and expect that it will help you shed pounds."

Making the results clinically useful "would involve finding a way to alter vitamin D receptor expression, and, as yet, it is not clear how to do that."

Feldman added that the goal would be 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."

Obtained from MedPageToday.Com

Nutrigenomics