Featured Research

from universities, journals, and other organizations

Possible Drug Target For Obesity Treatment A 'No-brainer'

Date:
February 9, 2009
Source:
University of North Carolina School of Medicine
Summary:
Scientists have discovered a gene that when mutated causes obesity by dampening the body's ability to burn energy while leaving appetite unaffected.

Scientists at the University of North Carolina at Chapel Hill School of Medicine have discovered a gene that when mutated causes obesity by dampening the body's ability to burn energy while leaving appetite unaffected.

The new research could potentially lead to new pharmacologic approaches to treating obesity in humans that do not target the brain, according to study senior author Yi Zhang, Ph.D., Howard Hughes Medical Institute investigator and professor of biochemistry and biophysics in the UNC School of Medicine. Zhang is also a member of the UNC Lineberger Comprehensive Cancer Center.

The findings also add new knowledge to the burgeoning field of epigenetics, in which heritable changes in gene expression or physical appearance are caused by mechanisms besides changes in the underlying DNA.

The gene in question encodes for a specific epigenetic factor, an enzyme called Jhdm2a. In 2006, Zhang showed that Jhdm2a was able to demethylate, or remove, a methyl group from one of four histone proteins bound to all genes. Because they are so intimately associated with DNA, even slight chemical alterations of histones can have profound effects on nearby genes.

The new study focused on a line of so-called "knockout" mice that lacked the Jhdm2a gene. Zhang found impairment in two molecular signaling pathways important for normal function in brown fat tissue and muscle cells. Both pathways exert a major influence on metabolism, the body's conversion of food to energy. Without the enzyme, the mice had reduced metabolisms, becoming visibly obese.

To Zhang's knowledge, this is the first mouse model to exhibit obese traits that do not resulting from an alteration in appetite, which is largely a brain function. "Given that this gene is not expressed in the brain, any drug that targets this gene would not have an effect on brain function," he said. "Therefore, we are really looking for a pure effect on metabolism."

With that in mind, Zhang anticipates that the study, published online February 4, 2009 in the journal Nature, could be of great interest to pharmaceutical companies eager to develop new anti-obesity drugs aimed at a novel, new molecular target expressed in non-brain tissues.

Zhang said his group will continue to look for more detailed mechanisms involved in how the enzyme regulates the relevant genes and changes in the metabolic rate.

"My lab has a long-term interest in identifying histone-modifying enzymes," said Zhang. "Three years ago, we discovered the jumanji family of histone demethylase, which is a huge family and brought big interest in the field to study this group of genes."

That body of work has contributed significantly to a new understanding that mutations in epigenetic factors such as histone demethylase enzymes can have profound physiologic effects. The team had already zeroed in on the Jhdm2a enzyme, showing in a 2007 Nature publication that the Jhdm2a gene is highly expressed in mouse testes and plays an important role in spermiogenesis, the final step in the production of a functional sperm cell. Male mice with the gene knocked out were infertile.

That discovery has provided researchers with a new potential cause for male infertility, just as the current study shows that the same genetic defect leads to obesity in both male and female animals, shedding new light on the role of epigenetics in regulating metabolism.

"So this gene has at least two biological functions," Zhang said. "One is control of spermiogenesis; the other is control of metabolism."

This finding was not necessarily expected by the researchers. "Nobody could have predicted that this gene had this particular function in regulating metabolism," Zhang said. "The histone-modifying enzymes actually have broad effect – every gene is packaged by histones. Therefore, when modifying histones, you can't necessarily predict what function will be affected."

In addition to being obese, the Jhdm2a knockout mouse also developed other characteristics related to human metabolic disorder, such as hyperlipidemia (raised lipid levels) and insulin resistance. Whether the mouse results will be mirrored in humans remains to be seen. "We don't know whether this gene is defective in some of the obese or metabolic syndrome patients – those are things that need to be investigated," Zhang said.

One of the lines of research Zhang and his colleagues will pursue is to conduct experiments with "conditional" knockout mouse models, in which the gene of interest is functionally removed from specific tissues, such as, in this case, brown fat or muscle tissue. According to Zhang, "that way we can ask specific questions and can pinpoint the specific tissue or cell types…then we can also pinpoint the specific molecular mechanism."

The study was supported by the Howard Hughes Medical Institute and the National Institutes of Health.

Study co-authors include postdoctoral fellows Keisuke Tateishi, M.D., Ph.D. and Yuki Okada, Ph.D.; and graduate student Eric Kallin.


Story Source:

The above story is based on materials provided by University of North Carolina School of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

University of North Carolina School of Medicine. "Possible Drug Target For Obesity Treatment A 'No-brainer'." ScienceDaily. ScienceDaily, 9 February 2009. <www.sciencedaily.com/releases/2009/02/090204161852.htm>.
University of North Carolina School of Medicine. (2009, February 9). Possible Drug Target For Obesity Treatment A 'No-brainer'. ScienceDaily. Retrieved September 30, 2014 from www.sciencedaily.com/releases/2009/02/090204161852.htm
University of North Carolina School of Medicine. "Possible Drug Target For Obesity Treatment A 'No-brainer'." ScienceDaily. www.sciencedaily.com/releases/2009/02/090204161852.htm (accessed September 30, 2014).

Share This



More Health & Medicine News

Tuesday, September 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

How 'Yes Means Yes' Defines Sexual Assault

How 'Yes Means Yes' Defines Sexual Assault

Newsy (Sep. 29, 2014) Aimed at reducing sexual assaults on college campuses, California has adopted a new law changing the standard of consent for sexual activity. Video provided by Newsy
Powered by NewsLook.com
Scientists May Have Found An Early Sign Of Pancreatic Cancer

Scientists May Have Found An Early Sign Of Pancreatic Cancer

Newsy (Sep. 29, 2014) Researchers looked at 1,500 blood samples and determined people who developed pancreatic cancer had more branched chain amino acids. Video provided by Newsy
Powered by NewsLook.com
Colo. Doctors See Cluster of Enterovirus Cases

Colo. Doctors See Cluster of Enterovirus Cases

AP (Sep. 29, 2014) Doctors at the Children's Hospital of Colorado say they have treated over 4,000 children with serious respiratory illnesses since August. Nine of the patients have shown distinct neurological symptoms, including limb weakness. (Sept. 29) Video provided by AP
Powered by NewsLook.com
Dr.'s Unsure of Cause of Fast-Spreading Virus

Dr.'s Unsure of Cause of Fast-Spreading Virus

AP (Sep. 29, 2014) Doctors at the Children's Hospital of Colorado say they have treated over 4,000 children with serious respiratory illnesses since August. Nine of the patients have shown distinct neurological symptoms, including limb weakness. (Sept. 29) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins