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Study shows how common obesity gene contributes to weight gain
Date:5/22/2014

ary cilium. "Aberrations in the cilium have been implicated in rare forms of obesity," said Dr. Leibel. "But it wasn't clear how this structure might be involved in garden-variety obesity."

Dr. Leibel and his colleague, George Stratigopoulos, PhD, associate research scientist, hypothesized that common FTO variations in noncoding regions of the gene do not change its primary function, which is to produce an enzyme that modifies DNA and RNA. Instead, they suspected that FTO variations indirectly affect the expression of RPGRIP1L. "When Dr. Stratigopoulos analyzed the sequence of FTO's intronits noncoding, or nonprotein-producing, portionwe found that it serves as a binding site for a protein called CUX1," said Dr. Leibel. "CUX1 is a transcription factor that modifies the expression of RPGRIP1L."

Next, Dr. Stratigopoulos set out to determine whether RPGRIP1L plays a role in obesity. He created mice lacking one of their two RPGRIP1L genes, in effect, reducing but not eliminating the gene's function. (Mice that lack both copies of the gene have several serious defects that would obscure the effects on food intake.) Mice with one copy of RPGRIP1L had a higher food intake, gained significantly more weight, and had a higher percentage of body fat than controls.

In a subsequent experiment, the CUMC team found that RPGRIP1L-deficient mice had impaired leptin signaling. "The receptors didn't convene properly on the cell surface around the base of cilium," said Dr. Leibel. "RPGRIP1L appears to play a role in getting leptin receptors to form clusters, where they are more efficient in signaling."

"Overall," said Dr. Leibel, "our findings open a window onto the possible role of the primary cilium in common forms of obesity."

The CUMC team is now conducting studies to learn more about the various components of the FTO- RPGRIP1L pathway, which ciliary proteins are affected by changes in this pathway, and how these proteins mediate act
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Contact: Karin Eskenazi
ket2116@cumc.columbia.edu
212-342-0508
Columbia University Medical Center
Source:Eurekalert

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