Polluted air increases obesity risk in young animals

ScienceDaily (Dec. 3, 2010) ? Exposure to polluted air early in life led to an accumulation of abdominal fat and insulin resistance in mice even if they ate a normal diet, according to new research.

Animals exposed to the fine-particulate air pollution had larger and more fat cells in their abdominal area and higher blood sugar levels than did animals eating the same diet but breathing clean air.

Researchers exposed the mice to the polluted air for six hours a day, five days a week for 10 weeks beginning when the animals were 3 weeks old. This time frame roughly matches the toddler years to late adolescence in humans.

The exposure levels for the animals subjected to polluted air resemble the fine-particulate pollution that can be found in urban areas in the United States.

"This is one of the first, if not the first, study to show that these fine particulates directly cause inflammation and changes in fat cells, both of which increase the risk for Type 2 diabetes," said Qinghua Sun, an associate professor of environmental health sciences at Ohio State University and lead author of the study.

The research appears in the December issue of the journal Arteriosclerosis, Thrombosis, and Vascular Biology.

Sun and colleagues fed the mice with either a normal diet or a high-fat diet and exposed them to either filtered air or air containing at least seven times more fine particulates than the ambient air in Columbus, Ohio. On average, the ambient air contained 15.8 micrograms of fine particles per cubic meter, compared to 111 micrograms per cubic meter in the concentrated air to which the mice were exposed.

According to the U.S. Environmental Protection Agency, roughly one out of every three people in the United States is at a higher risk of experiencing health effects related to the presence of polluted air. Because of their tiny size -- 2.5 micrometers or smaller in diameter, or about 1/30th of the average width of a human hair -- these particles could reach deep areas of the lungs and other organs in the body.

For this study, researchers obtained baseline measures of the mice for their weight, blood sugar and body fat at the start of the experiment. After exposing the animals to polluted or filtered air for 10 weeks, researchers analyzed the mice for a number of risk factors associated with obesity and insulin resistance, the hallmark of Type 2 diabetes.

As expected, mice on the high-fat diet gained much more weight than those on the normal diet. But mice exposed to polluted air and eating the normal diet had more significant elevations in glucose -- sugar in their blood -- than did normal-diet mice that breathed clean air. They also showed more signs of insulin resistance based on an index that measures both sugar and insulin in the blood at the same time.

Insulin resistance results when the presence of insulin does not initiate the transfer of glucose from the blood into the tissues, where it is used for energy.

Mice exposed to pollution -- regardless of which diet they ate --also had higher blood levels of tumor necrosis factor-alpha, a protein involved in systemic inflammation, than did mice breathing clean air.

In addition, both abdominal and subcutaneous (under the skin) types of fat were increased with exposure to pollution in mice, even in animals that ate the normal diet. Mice eating a high-fat diet also had more fat, but their exposure to polluted air did not exacerbate those effects.

"These findings suggest that fine particulate pollution exposure alone, in the presence of a normal diet, may lead to an increase in fat cell size and number, and also have a proinflammatory effect," said Sanjay Rajagopalan, senior author of the study and the John W. Wolfe Professor of Cardiovascular Medicine at Ohio State.

Fat cell size and quantity is important in many diseases because the tissue made up of fat cells begins to secrete molecules that send out complex signals. This process can lead to inflammation and, in turn, to insulin resistance or diabetes, as well as other disease conditions. Abdominal, or visceral, fat in particular is closely associated with the development of cardiovascular disease.

The scientists do not yet know whether these effects would be sustained over adult life if air quality circumstances were changed, or if they are otherwise reversible.

"We really wanted to see how this air pollution affects obesity with this early life exposure," Sun said. "In a real-world scenario, it would be very difficult to escape from the pervasive influence of dirty air, an influence that begins very early on in life."

A To explore the physiological mechanism behind the pollution's effects on fat cells and inflammation, the researchers tested the same exposure levels in mice that had been genetically modified so they don't carry a gene called p47phox. This gene is a subunit of an enzyme linked to free radicals that lead to the accumulation of inflammatory cells in artery walls and plaque, known as atherosclerosis.

Mice without this gene that were exposed to pollution did not show most of the effects of that exposure that normal mice showed, Sun said.

"When you knock out p47phox, it pretty much alleviates the effects of air pollution," he said. "What this gives us is a potential for future therapeutic options that might target this gene."

More research would be required to further define this mechanism, he noted.

These same researchers do plan to continue studying the effects of fine particulate pollution on health, and have designed a study in humans that will take place in Beijing, China. The project, led by Rajagopalan, will test the effects of air pollution on metabolic syndrome and insulin resistance in patients. Participants will wear personal monitors to gauge their exposure to pollution.

This research is supported by the National Institutes of Health and the Diabetes Action Research and Education Foundation.

Additional co-authors of the paper are Xiaohua Xu, Zubin Yavar and Matt Verdin of the Division of Environmental Health Sciences in Ohio State's College of Public Health; Zhekang Ying, Georgeta Mihai, Thomas Kampfrath and Aixia Wang of Ohio State's Davis Heart and Lung Research Institute; and Mianhua Zhong, Morton Lippmann and Lung-Chi Chen of New York University School of Medicine.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Ohio State University. The original article was written by Emily Caldwell.

Journal Reference:

X. Xu, Z. Yavar, M. Verdin, Z. Ying, G. Mihai, T. Kampfrath, A. Wang, M. Zhong, M. Lippmann, L.-C. Chen, S. Rajagopalan, Q. Sun. Effect of Early Particulate Air Pollution Exposure on Obesity in Mice: Role of p47phox. Arteriosclerosis, Thrombosis, and Vascular Biology, 2010; 30 (12): 2518 DOI: 10.1161/ATVBAHA.110.215350

Note: If no author is given, the source is cited instead.

View the original article here

New role for master regulator in cell metabolism, response to stress: Clinical implications for obesity, diabetes and cancer research

ScienceDaily (Oct. 6, 2010) ? AMP-activated protein kinase, or AMPK, is a master regulator protein of metabolism that is conserved from yeast to humans. When a cell is low on fuel, AMPK shuts down processes that use energy and turns on processes that produce energy.

Biologists have been studying how AMPK works for several decades and know that once it is activated, AMPK turns on a large number of genes by passing the "make more energy" message through numerous signaling cascades in the cell. What was not known, until now, was that AMPK also works via an epigenetic mechanism to slow down or stop cell growth.

Shelley Berger, PhD, Daniel S. Och University Professor and director of the Epigenetics Program at the University of Pennsylvania, and David Bungard, PhD, a postdoctoral fellow in the Berger lab at the University of Pennsylvania School of Medicine, in collaboration with Craig Thompson, MD, director of the Abramson Cancer Center at Penn, and Russell G. Jones, PhD, Goodman Cancer Centre at McGill University, found that AMPK binds directly to sites on chromosomes called promoters that regulate gene expression related to cell metabolism.

They published their findings online in Science Express.

Unlike genetic changes, which involve a change or mutation in DNA sequence, epigenetic changes in the nucleus leave the DNA sequence unaltered but modify the histone proteins, which comprise the backbone of the chromosome. Histones are proteins found in the nucleus that package and order DNA into structural units. Epigentic changes alter how DNA folds in chromosomes, changing how accessible genes are to regulatory proteins and enzymes that copy genes into RNA messages.

"Epigenetics is the study of how factors outside of actual DNA interact with, but not alter, genes. It is turning out, through recent discoveries, that epigenetic information plays an important role in human health and disease," says Berger.

"Our results show a direct link between the energy state of the cell and its epigenetic status," adds Bungard.

Thus far, the investigators have identified two genes that are regulated by AMPK at the histone level in the nucleus. These initial observations were made in tissue-culture cells and the team is now working to confirm them in animal models.

AMPK's main role is to sense cell stress. In this study, cells were stressed with ultraviolet radiation and low levels of glucose, a common source of cell energy. In the sequence of events after stress, AMPK picks up the cell-stress signal and travels to the nucleus to bind to the important tumor suppressor p53 protein. This in turn, causes a phosphate to be added to a histone near the p21 gene, which turns the gene on. The function of p21 is to stop or slow down the cell cycle until energy levels are restored to normal.

The same mechanism occurs at other genes regulated by AMPK, allowing direct control of the many processes that AMPK regulates. These processes, such as sugar storage, insulin production, and other pathways, are altered in obesity and diabetes.

The researchers were surprised by these findings on many fronts: This is the first time that investigators have shown that AMPK is present on chromatin, that it targets histones, and that p53 is involved in sensing stress via AMPK. Other stress-response proteins could use similar epigenetic pathways, and thus may be a common way that cells respond to stress.

The work conducted by the team holds out promise for new therapies for a number of diseases, including diabetes and cancer. For example, AMPK is a target of metformin, the most commonly prescribed drug for the treatment of Type II diabetes. Understanding how AMPK can directly change gene expression may lead to the identification of new disease-associated targets and potential therapies.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Pennsylvania School of Medicine.

Journal Reference:

David Bungard, Benjamin J. Fuerth, Ping Y. Zeng, Brandon Faubert, Nancy L. Mass, Benoit Viollet, David Carling, Craig B. Thompson, Russell G. Jones, and Shelley L. Berger. Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation. Science, 2010; DOI: 10.1126/science.1191241

Note: If no author is given, the source is cited instead.

View the original article here

In childhood obesity, gene variants raise risk, study finds

ScienceDaily (Oct. 15, 2010) ? A new study by pediatric researchers has added to the evidence that genes have a strong influence on childhood obesity.

The study team searched across the whole genomes of thousands of obese children for copy number variations (CNVs)--deletions or duplications of DNA sequences. Although the CNVs they found are rare within the population, their data suggest that those individuals harboring such variants are at a very high risk of becoming obese.

"Our study is the first large-scale, unbiased genome-wide scan of CNVs in common pediatric obesity," said study leader Struan F.A. Grant, Ph.D., associate director of the Center for Applied Genomics (CAG) at The Children's Hospital of Philadelphia. "We found CNVs that were exclusive to obese children across two ethnicities -- European Americans and African Americans."

The study appears online in the American Journal of Human Genetics. Grant, along with co-study leader Hakon Hakonarson, M.D., Ph.D., director of the CAG, led a team based at The Children's Hospital of Philadelphia and the University of Pennsylvania.

A major health problem in Western societies, obesity has increased dramatically in prevalence in both children and adults over the past decade. Associated with insulin resistance, obesity is a risk factor for type 2 diabetes, heart disease, hypertension and other chronic illnesses. Approximately 70 percent of obese teenagers grow up to become obese adults.

Public health experts have implicated environmental contributors to obesity, such as sedentary lifestyles and the wide availability of high-calorie convenience foods. However, from twin studies and other research, scientists have also recognized that obesity has a strong genetic component as well, although this has been analyzed more frequently in adults than in children.

In the current study, the researchers searched for CNVs in a European American cohort of 1,080 obese children and a control group 2,500 lean children. The obese children were in the top 5th percentile of body mass index, but to avoid confounding their data, the researchers excluded the most severe cases, many of whom were likely to have complicated medical syndromes. After identifying multiple CNVs occurring in the obese children but not the lean controls, the researchers replicated the study in a different cohort, all African American children: 1,479 obese subjects and 1,575 lean controls. All the children were between ages two and 18, recruited from The Children's Hospital of Philadelphia pediatric network.

Of the 17 CNVs they found in obese European Americans, eight, or nearly half, also occurred in obese African Americans. "Because many gene variants have different frequencies in different ethnic groups, detecting these same CNVs in both groups, exclusively in obese subjects, strengthens the probability that these CNVs play a genuine role in the development of obesity," said Hakonarson.

The majority of the genes located at the CNV sites were not previously reported to be associated with obesity. However, at one location, near the gene ARL15, researchers previously linked a gene variant with a higher risk of coronary heart disease and type 2 diabetes via levels of adiponectin, a hormone involved in glucose regulation.

The current study does not have immediate applications to diagnosis and treatment, but adds another piece to the puzzle of understanding childhood obesity. Grant added that further studies at Children's Hospital and elsewhere will uncover additional genetic influences, and functional studies will investigate the biological details of how genes contribute to childhood obesity. Such knowledge may provide a basis for designing preventive measures and treatments.

Financial support for the study came from The Children's Hospital of Philadelphia, the National Institutes of Health and the Cotswold Foundation.

"A Genome-Wide Study Reveals Copy Number Variants Exclusive to Childhood Obesity Cases," American Journal of Human Genetics, published online Oct. 14, 2010.

Editor's Note: This article is not intended to provide medical advice, diagnosis or treatment.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Children's Hospital of Philadelphia, via EurekAlert!, a service of AAAS.

Journal Reference:

joseph T. Glessner, Jonathan P. Bradfield, Kai Wang, Nagahide Takahashi, Haitao Zhang, Patrick M. Sleiman, Frank D. Mentch, Cecilia E. Kim, Cuiping Hou, Kelly A. Thomas, Maria L. Garris, Sandra Deliard, Edward C. Frackelton, F. George Otieno, Jianhua Zhao, Rosetta M. Chiavacci, Mingyao Li, Joseph D. Buxbaum, Robert I. Berkowitz, Hakon Hakonarson, Struan F.A. Grant. A Genome-wide Study Reveals Copy Number Variants Exclusive to Childhood Obesity Cases. American Journal of Human Genetics, 2010; DOI: 10.1016/j.ajhg.2010.09.014

Note: If no author is given, the source is cited instead.

View the original article here