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 High in calories and low in nutrients when adolescents share pictures of food online
07.04.2016 | University of Gothenburg

nachricht Brain connectivity reveals hidden motives
04.03.2016 | Universität Zürich

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: Worldwide Success of Tyrolean Wastewater Treatment Technology

A biological and energy-efficient process, developed and patented by the University of Innsbruck, converts nitrogen compounds in wastewater treatment facilities into harmless atmospheric nitrogen gas. This innovative technology is now being refined and marketed jointly with the United States’ DC Water and Sewer Authority (DC Water). The largest DEMON®-system in a wastewater treatment plant is currently being built in Washington, DC.

The DEMON®-system was developed and patented by the University of Innsbruck 11 years ago. Today this successful technology has been implemented in about 70...

Im Focus: Computational high-throughput screening finds hard magnets containing less rare earth elements

Permanent magnets are very important for technologies of the future like electromobility and renewable energy, and rare earth elements (REE) are necessary for their manufacture. The Fraunhofer Institute for Mechanics of Materials IWM in Freiburg, Germany, has now succeeded in identifying promising approaches and materials for new permanent magnets through use of an in-house simulation process based on high-throughput screening (HTS). The team was able to improve magnetic properties this way and at the same time replaced REE with elements that are less expensive and readily available. The results were published in the online technical journal “Scientific Reports”.

The starting point for IWM researchers Wolfgang Körner, Georg Krugel, and Christian Elsässer was a neodymium-iron-nitrogen compound based on a type of...

Im Focus: Atomic precision: technologies for the next-but-one generation of microchips

In the Beyond EUV project, the Fraunhofer Institutes for Laser Technology ILT in Aachen and for Applied Optics and Precision Engineering IOF in Jena are developing key technologies for the manufacture of a new generation of microchips using EUV radiation at a wavelength of 6.7 nm. The resulting structures are barely thicker than single atoms, and they make it possible to produce extremely integrated circuits for such items as wearables or mind-controlled prosthetic limbs.

In 1965 Gordon Moore formulated the law that came to be named after him, which states that the complexity of integrated circuits doubles every one to two...

Im Focus: Researchers demonstrate size quantization of Dirac fermions in graphene

Characterization of high-quality material reveals important details relevant to next generation nanoelectronic devices

Quantum mechanics is the field of physics governing the behavior of things on atomic scales, where things work very differently from our everyday world.

Im Focus: Graphene: A quantum of current

When current comes in discrete packages: Viennese scientists unravel the quantum properties of the carbon material graphene

In 2010 the Nobel Prize in physics was awarded for the discovery of the exceptional material graphene, which consists of a single layer of carbon atoms...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking 4.0: International Laser Technology Congress AKL’16 Shows New Ways of Cooperations

24.05.2016 | Event News

Challenges of rural labor markets

20.05.2016 | Event News

International expert meeting “Health Business Connect” in France

19.05.2016 | Event News

 
Latest News

11 million Euros for research into magnetic field sensors for medical diagnostics

27.05.2016 | Awards Funding

Fungi – a promising source of chemical diversity

27.05.2016 | Life Sciences

New Model of T Cell Activation

27.05.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>