Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study shows how common obesity gene contributes to weight gain

23.05.2014

Affects a second gene linked to a hair-like appendage on brain cells

Researchers have discovered how a gene commonly linked to obesity—FTO—contributes to weight gain. The study shows that variations in FTO indirectly affect the function of the primary cilium, a little-understood hair-like appendage on brain and other cells. Specific abnormalities of cilium molecules, in turn, increase body weight, in some instances, by affecting the function of receptors for leptin, a hormone that suppresses appetite. The findings, made in mice, suggest that it might be possible to modify obesity through interventions that alter the function of the cilium, according to scientists at Columbia University Medical Center (CUMC).

"If our findings are confirmed, they could explain how common genetic variants in the gene FTO affect human body weight and lead to obesity," said study leader Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, professor of pediatrics and medicine, and co-director of the Naomi Berrie Diabetes Center at CUMC. "The better we can understand the molecular machinery of obesity, the better we will be able to manipulate these mechanisms and help people lose weight."

The study was published on May 6 in the online edition of Cell Metabolism.

... more about:
»CUMC »Diabetes »FTO »Mice »noncoding »obesity »primary »variations »weight

Since 2007, researchers have known that common variants in the fat mass and obesity-associated protein gene, also known as FTO, are strongly associated with increased body weight in adults. But it was not understood how alterations in FTO might contribute to obesity. "Studies have shown that knocking out FTO in mice doesn't necessarily lead to obesity, and not all humans with FTO variants are obese," said Dr. Leibel. "Something else is going on at this location that we were missing."

In experiments with mice, the CUMC team observed that as FTO expression increased or decreased, so did the expression of a nearby gene, RPGRIP1L. RPGRIP1L is known to play a role in regulating the primary 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 intron—its noncoding, or nonprotein-producing, portion—we 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 actions of leptin receptors.

###

The paper is titled, "Hypomorphism for RPGRIP1L, a Ciliary Gene Vicinal to the FTO Locus, Causes Increased Adiposity in Mice." The other contributors are Jayne F. Martin Carli (CUMC), Diana R. O'Day (University of Washington, Seattle, WA), Liheng Wang (CUMC), Charles A. LeDuc (CUMC), Patricia Lanzano (CUMC), Wendy K. Chung (CUMC), Michael Rosenbaum (CUMC), Dieter Egli (CUMC), and Daniel A. Doherty (University of Washington).

The authors declare no financial or other conflicts of interests.

The study was supported by grants from the National Institutes of Health (DK52431-15, DK26687-30, NS064077, and DK097399-01).

The Naomi Berrie Diabetes Center at CUMC opened in 1998 to serve the 1.6 million people with diabetes in the New York area, by combining world-class diabetes research and education programs with family-oriented patient care. Founded with support from the Russell Berrie Foundation and other friends, the center is named in honor of the mother of the late Russell Berrie, founder of RUSS™ Toys. The center's more than 100 faculty and students conduct basic and clinical research related to the pathogenesis and treatment of all forms of diabetes and its complications. For more information, visit http://www.nbdiabetes.org.

Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Columbia University Medical Center is home to the largest medical research enterprise in New York City and State and one of the largest faculty medical practices in the Northeast. For more information, visit cumc.columbia.edu or columbiadoctors.org.

Karin Eskenazi | Eurek Alert!

Further reports about: CUMC Diabetes FTO Mice noncoding obesity primary variations weight

More articles from Studies and Analyses:

nachricht Is Marriage Good or Bad for the Figure?
29.06.2015 | Max-Planck-Institut für Bildungsforschung

nachricht Fructose produces less rewarding sensations in the brain
25.06.2015 | Universität Basel

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: X-rays and electrons join forces to map catalytic reactions in real-time

New technique combines electron microscopy and synchrotron X-rays to track chemical reactions under real operating conditions

A new technique pioneered at the U.S. Department of Energy's Brookhaven National Laboratory reveals atomic-scale changes during catalytic reactions in real...

Im Focus: Iron: A biological element?

Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and a half billion years ago.

Think of an object made of iron: An I-beam, a car frame, a nail. Now imagine that half of the iron in that object owes its existence to bacteria living two and...

Im Focus: Thousands of Droplets for Diagnostics

Researchers develop new method enabling DNA molecules to be counted in just 30 minutes

A team of scientists including PhD student Friedrich Schuler from the Laboratory of MEMS Applications at the Department of Microsystems Engineering (IMTEK) of...

Im Focus: Bionic eye clinical trial results show long-term safety, efficacy vision-restoring implant

Patients using Argus II experienced significant improvement in visual function and quality of life

The three-year clinical trial results of the retinal implant popularly known as the "bionic eye," have proven the long-term efficacy, safety and reliability of...

Im Focus: Lasers for Fast Internet in Space – Space Technology from Aachen

On June 23, the second Sentinel mission was launched from the space mission launch center in Kourou. A critical component of Aachen is on board. Researchers at the Fraunhofer Institute for Laser Technology ILT and Tesat-Spacecom have jointly developed the know-how for space-qualified laser components. For the Sentinel mission the diode laser pump module of the Laser Communication Terminal LCT was planned and constructed in Aachen in cooperation with the manufacturer of the LCT, Tesat-Spacecom, and the Ferdinand Braun Institute.

After eight years of preparation, in the early morning of June 23 the time had come: in Kourou in French Guiana, the European Space Agency launched the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference on Regenerative Medicine in Leipzig: Last chance to submit abstracts until 2 July

25.06.2015 | Event News

World Conference on Regenerative Medicine: Abstract Submission has been extended to 24 June

16.06.2015 | Event News

MUSE hosting Europe’s largest science communication conference

11.06.2015 | Event News

 
Latest News

Europeans have unknowingly contributed to the spread of invasive plant species in North America

01.07.2015 | Ecology, The Environment and Conservation

Graphene flexes its electronic muscles

01.07.2015 | Materials Sciences

Physical study may give boost to hydrogen cars

01.07.2015 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>