Corporate Banner
Satellite Banner
Genomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Researchers Identify ‘Fat Gene’ Associated with Obesity

Published: Monday, March 17, 2014
Last Updated: Monday, March 17, 2014
Bookmark and Share
Mutations within the gene FTO have been implicated as the strongest genetic determinant of obesity risk in humans, but the mechanism behind this link remained unknown.

Now an international team of scientists has discovered that the obesity-associated elements within FTO interact with IRX3, a distant gene on the genome that appears to be the functional obesity gene. The FTO gene itself appears to have only a peripheral effect on obesity, researchers report in the March 12 online of Nature.

“Our data strongly suggest that IRX3 controls body mass and regulates body composition,” said senior study author Marcelo Nobrega, associate professor of human genetics at the University of Chicago. “Any association between FTO and obesity appears due to the influence of IRX3.”

Mutations to introns (noncoding portions) of the gene FTO have been widely investigated after genome-wide association studies revealed a strong link between FTO and obesity and diabetes. Yet overexpressing or deleting FTO in animal models affects whole body mass and composition, not just fat, and experiments have failed to show that these obesity-linked introns affect the function of the FTO gene itself.

Hoping to explain these observations, Nobrega and his team mapped the behavior of promoters—regions of DNA that activate gene expression—located within one million base pairs on either side of the FTO gene. In adult mice brains, in which FTO was thought to affect metabolic function, they discovered that the promoter that turns on FTO did not interact with obesity-associated FTO introns.

“Instead, we found that the promoter for IRX3, a gene several hundred thousand base pairs away, did interact with these introns, as well as a large number of other elements across the vast genetic distance we studied,” said co-author Jose Luis Gomez-Skarmeta, a geneticist at the Andalusian Center of Developmental Biology in Sevilla, Spain. The researchers found a similar pattern of interactions in humans after analyzing data from the ENCODE project, which they confirmed with experiments on human cells.

Using data from 153 brain samples from individuals of European ancestry, they discovered that the mutations to FTO introns that affected body weight are associated with IRX3 expression, but not FTO. Obesity-related FTO introns enhanced the expression of IRX3, functioning as regulatory elements. The FTO gene itself did not appear to play a role in this interaction.

“Regulatory elements are switches that turn genes on and off. What we’ve found is that the switches that control IRX3 are far away from the gene and actually inside the FTO gene", said Nobrega.

IRX3-DEFICIENT MICE ARE THIN
To verify the role of IRX3, the researchers engineered mice without the IRX3 gene. These mice were significantly leaner than their normal counterparts. They weighed about 30 percent less, primarily through reduced fat.

The decrease in weight gain occurred despite normal levels of food consumption and physical activity. When fed a high-fat diet, mice without IRX3 retained the same weight and fat levels as on normal diets. Normal mice fed a high-fat diet gained almost twice as much weight. Fat cells in IRX3-deficient mice were smaller, and increased levels of brown fat were observed. In addition, these mice were better able to process glucose.

“These mice are thin. They lose weight primarily through the loss of fat. But they are not runts,” said co-author Chin-Chung Hui, professor of molecular genetics at the University of Toronto. “They are also completely resistant to high-fat, diet-induced obesity. They have much better ability to handle glucose and seem protected against diabetes.”

The researchers also discovered that mice with altered IRX3 function in the hypothalamus, the portion of the brain known to regulate feeding behavior and energy expenditure, showed an identical pattern of leanness as mice which completely lacked IRX3. Hypothalamic function of IRX3, therefore, appears to control body mass and composition in these animals, indicating that the genetic predisposition to obesity is wired in the brain.

IRX3 codes for a protein that regulates other genes, and is present both in and outside the brain, in organs and cells such as fat cells. Nobrega and his team are currently investigating how IRX3 interacts with genes and molecules that it regulates, and hope to identify targets for the development of novel therapies against obesity and diabetes.

“IRX3 is probably a master regulator of genetic programs in the cells where it is expressed,” Nobrega said. “We’re interested in what its targets are and what they alter. The goal is to identify downstream targets of IRX3 that become models for drug targeting.”

The study, “Obesity-associated variants within FTO form long-range functional connections with IRX3,” was funded by the National Institutes of Health. Additional authors include Scott Smemo, Juan Tena, Kyoung-Han Kim, Eric Gamazon, Noboru Sakabe, Carlos Gomez-Marın, Ivy Aneas, Flavia Credidio, Debora Sobreira, Nora Wasserman, Ju Hee Lee, Vijitha Puviindran, Davis Tam, Michael Shen, Joe Eun Son, Niki Alizadeh Vakili, Hoon-Ki Sung, Silvia Naranjo, Rafael Acemel, Miguel Manzanares, Andras Nagy, Nancy Cox, Chi-Chung Hui and Jose Luis Gomez-Skarmeta


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,300+ scientific posters on ePosters
  • More than 5,000+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Grad Student's Finding Enables Rapid Compound Screening
Grad student makes technical leap that could enable rapid screening of anti-cancer compounds.
Friday, August 19, 2016
From Fins to Fingers
New gene-editing methods help the mapping of cells linking fish fins and mammalian limbs.
Friday, August 19, 2016
New Technique Targets Ataxia Gene
Scientists selectively turn off the disease-causing portion of a gene that causes a severe form of ataxia.
Thursday, July 14, 2016
New Microbiome Center to Merge Expertise of UChicago, MBL and Argonne
Researchers to study world of microbes across environments.
Wednesday, May 18, 2016
New Code for Control of Gene Expression
A new cellular signal discovered by a team of scientists at the University of Chicago and Tel Aviv University provides a promising new lever in the control of gene expression.
Thursday, February 18, 2016
Enormous Genetic Variation May Shield Tumors from Treatment
Debate over Darwinian selection vs. random mutations emerges at the tumor level.
Wednesday, November 11, 2015
Gut Bacteria Can Dramatically Amplify Cancer Immunotherapy
Manipulating microbes maximizes tumor immunity in mice.
Monday, November 09, 2015
New Form of DNA Modification May Carry Inheritable Information
Scientists have described the surprising discovery and function of a new DNA modification in insects, worms and algae.
Friday, May 08, 2015
Genetic Analysis Reveals Insights into Genetics of OCD, Tourette’s
Major differences between the genetic makeup of obsessive-compulsive disorder and Tourette’s syndrome, providing the first direct confirmation that both are highly heritable.
Tuesday, November 05, 2013
Humans and Chimps Share Genetic Strategy in Battle Against Pathogens
Findings point to common ancestry.
Tuesday, February 19, 2013
Graeme Bell Receives International Diabetes Prize
Prize includes a certificate of honor, a Japanese objet d’art and a $150,000 prize.
Tuesday, December 18, 2012
Study Points to New Target for Cancers Resistant to Certain Drugs
A more sensitive method to analyze protein interactions has uncovered a new way that cancer cells may use the cell-surface molecule HER3 to drive tumor progression following treatment with HER1 and HER2 inhibitors.
Tuesday, September 11, 2012
Grapefruit Juice Lets Patients Take Lower Dose of Cancer Drug
First cancer study to harness drug-food interaction.
Thursday, August 09, 2012
Guidelines for Prostate Screening Widely Ignored, Study Finds
2008 recommendations from federal task force had no impact.
Monday, April 30, 2012
Chicago Cancer Genome Project Studies Genetics of 1,000 Tumors
Analyzing the genetics of cancers from different parts of the body may reveal surprising details for treatment and prevention.
Tuesday, December 29, 2009
Scientific News
Novel MRI Technique Distinguishes Healthy Prostate Tissue from Cancer
The UTSW researchers have determined that glucose stimulates release of the zinc ions from inside epithelial cells, which they could then track on MRIs.
Eye Colour Determines Cancer Risk
Researchers report first findings of a link between eye pigment gene and uveal melanoma development.
Telomere Replenishment in Real Time
Researchers have visualised the process of telomere attachment to chromosomes through single-molecule imaging.
Converting Isolated Cells with Gene Editing
Researchers have used CRISPR to generate neuronal cells from isolated connective tissue.
New Inflammatory Disease Discovered
NIH researchers have discovered a rare and potentially deadly disease - otulipenia - the mostly affects children.
Gene Linked to Hearing Loss Identified
Researchers have identifed a gene associated with age-related hearing loss.
Oxygen Content Contributes to Cancer
Research project concludes lack of oxygen in tumour cells changes cell gene expression, contributing to the growth of cancer.
Grad Student's Finding Enables Rapid Compound Screening
Grad student makes technical leap that could enable rapid screening of anti-cancer compounds.
From Fins to Fingers
New gene-editing methods help the mapping of cells linking fish fins and mammalian limbs.
Personalised Medicine: Dose by Design
Personalised medicine holds the promise of a new approach to healthcare, tailored exactly to our individual needs, as Congenica's Nick Lench discussed on a recent BBC Radio 4 programme.
Skyscraper Banner

SELECTBIO Market Reports
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,300+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,000+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!