New Insights Into Genes and Obesity Point to Possible Targets for Treatment

New research reveals association between body mass index and levels of DNA tagging of certain genes. Image: Jeff Morin/iStock.com

New research suggests that body mass index is linked to differing levels of DNA methylation in the HIF3A gene. Image: Jeff Morin/iStock.com

Researchers have found that potentially modifiable chemical tagging of a particular gene is associated with obesity in humans, a finding that underscores the complex roots of obesity involving interactions among lifestyle, genetics, and the environment.

Certain genes such as leptin can play a role in obesity, and the increasing use of whole-genome analysis has uncovered dozens of other genes that might contribute to the problem. In mice, studies have also shown that chemical tagging of some genes is linked with obesity. Such tagging, which is influenced by factors in the environment (including the diet), is part of a phenomenon known as epigenetic modification, which affects how genes are expressed by cells. A common type of epigenetic modification is DNA methylation, the reversible addition of a chemical methyl group to parts of DNA. While one’s genetics are predetermined and remain mostly unchanged throughout life (unless a spontaneous mutation occurs), one’s epigenetics are highly dynamic.

Now, a new study released yesterday in The Lancet reveals that DNA methylation of a specific gene involved in oxygen metabolism and energy expenditure in humans appears to be highly linked to body mass index (BMI) in a large population of Europeans.

Scientists at the University of Leicester in England performed genetic analyses on blood samples from 459 individuals of European origin and looked for associations between levels of methylation on various DNA segments and BMI. After searching through the entire DNA sequence, they found 3 segments on 1 gene, HIF3A, which had differing levels of DNA methylation that were significantly correlated with BMI, even after adjustment for other potentially confounding variables.

The researchers found that for every 10% increase in methylation level of these 3 segments of DNA—on a scale from 0 (no methylation) to 100% (full methylation)—BMI increased from 3.2% to 7.8%. In other words, in this particular population, for every 10% increase in HIF3A methylation level, there was an average BMI increase of 0.87 to 2.12 kg/m2.

When the researchers then tested 2 separate populations to see if the results could be replicated (1 group of 339 individuals from France and another group of 1789 individuals from Germany), they found that the associations still held true, although they were less strong. They also tested a fourth group of individuals, using either fat tissue or skin tissue rather than blood. They found an even stronger association between BMI and HIF3A methylation level in fat tissue, but no association in skin tissue.

The authors note that because this was a cross-sectional study, no conclusions about causality can be made. However, they said the findings provide a strong foundation for further research to understand the link between epigenetic changes and obesity, and that understanding the role such changes play could “identify novel therapeutic targets” for this widespread condition.

FDA Proposes Food Labeling Changes To Update Serving Sizes, Highlight Caloric Content

After 20 years, the familiar Nutrition Facts label on most food packages in the United States is finally getting a face-lift.

Today, the US Food and Drug Administration (FDA) announced several proposed changes to the Nutrition Facts box on food labels, which was originally created with the goal of making it easier for consumers to make healthier food choices. The proposed changes, which are currently still in draft form but will be formally published on March 3, reflect new research on the relationship between nutrition and chronic disease, as well as the evolving food consumption patterns in US consumers.

Some of the specific changes include:

  1. Replacing the current “recommended” serving size for a product with one that more accurately represents what people actually consume as a  serving, even if it exceeds the ideal size.

For example, the current serving size for ice cream on US food labels is a half-cup, containing approximately 200 calories. But in reality, people consume closer to 1 cup of ice cream per serving. Thus, the new label would depict a 1-cup, 400-calorie serving size rather than a half-cup, 200-calorie serving size. Similarly, for sodas, because most people consume an entire can or bottle as 1 serving, the serving size would be either 12 or 20 ounces, depending on the size of the bottle.

The FDA's new serving size concept. Source: fda.gov.

The FDA’s proposed new concept of serving size. Source: fda.gov.

  1. Making the number of calories per serving more prominent.
  2. Requiring the amount of “added sugars” per serving to be included.
  3. Changing the reference (or recommended) daily intake values for certain nutrients based on new evidence compiled by the Institute of Medicine and the Dietary Guidelines for Americans. For example, daily reference calcium intake will increase from 1000 mg to 1300 mg, and daily reference sodium intake will decrease from 2400 mg daily to 2300 mg daily.
  4. Revising the list of specific nutrients for which information on percent daily value (% DV) would  always be required. Information on vitamins A and C will no longer be required; instead, % DV for vitamin D and potassium will be required.

Here are examples of a current label (left) and its counterpart under the proposed new labeling rules (right):

Current (left) and proposed (right) Nutrition Facts labels. Source: fda.gov.

“Over half of American adults use this label on a regular basis,” said Michael Taylor, JD, the FDA’s deputy commissioner for foods and veterinary medicine, in a press conference today. He said that the FDA is hopeful that the labeling changes will help people make healthier food choices.

The FDA will be accepting public comment on the proposed changes for 90 days, after which a final decision will be made for the label’s new look.

Caffeine Intake of Children Unchanged Despite Increased Consumption of Coffee and Energy Drinks

Although coffee drinking has increased among children and adolescents, consumption of caffeinated soda has decreased. (Image: Nick_Thompson/iStock.com)

Although coffee drinking has increased among children and adolescents, consumption of caffeinated soda has decreased. (Image: Nick_Thompson/iStock.com)

The growing popularity of coffee and energy drinks among children and adolescents has prompted concerns about increased caffeine consumption in these populations. A study appearing today in Pediatrics showing that caffeine levels have been holding steady among US children and teens in recent years may at least mitigate that concern.

Caffeine, which increases the heart rate, blood pressure, speech rate, motor activity, gastric secretion, urination, and temperature, may affect the developing neurological and cardiovascular systems in children, according to the American Academy of Pediatrics (AAP). The group says that “caffeine and other stimulant substances contained in energy drinks have no place in the diets of children and adolescents.”

Researchers with the US Centers for Disease Control and Prevention (CDC) found that between 1999-2000 and 2009-2010, a steady 73% of children and adolescents reported consuming caffeine on a given day. The researchers based this conclusion on data from the National Health and Nutrition Examination Survey (NHANES), which is conducted every 2 years—specifically, data comprising 24-hour dietary recall information from participants aged 2 through 22 years.

Coffee consumption accounted for about 10% of caffeine intake for children and adolescents in 1999-2000 and increased to almost 24% in 2009-2010. Energy drinks, which did not exist in 1999-2000, accounted for almost 6% of caffeine intake in 2009-2010, but those increases were offset by decreases in caffeinated soda consumption, from 62% in 1999-2000 to 38% in 2009-2010. Overall mean caffeine intake among all children and adolescent consumers of caffeinated products declined from 77.4 mg/d in 1999-2000 to 58.1 mg/d in 2009-2010.

The researchers said their findings provide a baseline for caffeine intake among children and young adults and should allow other researchers to monitor whether the increasing consumption of coffee and energy drinks ultimately leads to higher overall caffeine consumption in these populations.

Should the Sun Set on Further Vitamin D Trials?

Current evidence is sufficient enough to show that vitamin D doesn’t prevent a variety of diseases, according to researchers in New Zealand. (Image: JAMA, ©AMA)

Current evidence is sufficient enough to show that vitamin D doesn’t prevent a variety of diseases, according to researchers in New Zealand. (Image: JAMA, ©AMA)

It may be time to pull the plug on future clinical trials examining whether vitamin D supplements prevent a variety of diseases, according to researchers at the University of Auckland in New Zealand.

The investigators analyzed findings from 40 randomized controlled trials aimed at determining whether vitamin D supplements, with or without calcium, may prevent heart attack, stroke, cancer, bone fractures, or death. Their study included a “futility analysis,” which determines whether the existing evidence is consistent and extensive enough to make additional research unnecessary.

In this case, the investigators calculated that current evidence would have to show the supplements reduced the risk of those diseases by at least 15% or decreased the risk of death by 5% or more to make further research worthwhile.

According to their results, published online today in The Lancet Diabetes & Endocrinology, vitamin D supplements, with or without calcium, did not meet the 15% threshold for heart attack, cancer, stroke, and bone fractures in the general public. However, findings showed that vitamin D with calcium may reduce hip fractures in elderly people living in nursing homes. Results on reducing the risk of death were inconclusive.

“The absence of findings in [a] large number of trials completed this far suggests that similar future trials will have a high chance of null or negative results and therefore might be viewed as a low priority by research funders,” the investigators wrote. Researchers and funding agencies alike should consider the “probable futility” of additional trials examining vitamin D’s effects on the diseases covered in their analysis, they added.

In an accompanying editorial, Karl Michaëlsson, MD, of the surgical sciences department at Uppsala University in Sweden, noted that recent US vitamin D supplement sales increased more than 10-fold, from $24 million in 2002 to $605 million in 2011.

Michaëlsson also noted ongoing uncertainties about the need for vitamin D supplements—varying recommendations on the blood level that constitutes insufficiency or deficiency and whether serum concentrations are directly linked with health outcomes. High-dose vitamin D supplements have been associated with an increased risk of fractures and falls, he added.

“It would be prudent to choose a cautious approach to vitamin D supplementation and to put more emphasis on the development of evidence-based cutoff points for vitamin D inadequacy,” Michaëlsson wrote.

Coffee Hydrates as Well as Water, Study Says

New research dispels the belief that coffee drinking causes dehydration. (Image: marcomayer/iStock.com)

New research dispels the belief that coffee drinking causes dehydration. (Image: marcomayer/iStock.com)

Researchers in England have reassuring news for coffee lovers worried that their daily dose of java may leave them dehydrated: a few cups of joe count the same toward a person’s fluid needs as an equal amount of water.

The belief that caffeinated drinks such as coffee could cause dehydration is based on a 1928 study that demonstrated caffeine’s diuretic effect. Since then, only 2 studies have tried to show whether evidence exists to support that belief. Results were mixed, so investigators at the University of Birmingham in England devised new research to compare whether drinking coffee affected hydration differently than water consumption.

“Our research aimed to establish if regular coffee consumption, under normal living conditions, is detrimental to the drinker’s hydration status,” lead author Sophie Killer, a doctoral researcher, said in a statement. The study was published online today in the journal PLOS ONE.

Killer and her colleagues enrolled 50 men, all moderate coffee drinkers who didn’t take diuretics or caffeine-containing medication. Women weren’t included in the study because menstrual cycles may cause fluid balance fluctuations. In the study’s first phase, investigators randomly assigned the men to drink 4 cups of black coffee or an equal amount of water daily for 3 consecutive days. After a 10-day “wash-out” period, the groups switched. Coffee drinkers changed to water and vice versa.

The investigators analyzed hydration status with several established measures—body mass, total body water, and blood and urine tests. They found the hydration effects of coffee or water did not differ significantly. The study participants lost a small but significant amount of body mass each day during both study phases, 0.2%. Several factors may explain the body mass loss, the investigators wrote. One possibility is that the men simply didn’t drink enough fluids during the study. Even so, the men weren’t near the clinical dehydration level of 1% to 3% body mass loss, the investigators noted.

“Consumption of a moderate intake of coffee, 4 cups per day, in regular coffee-drinking males caused no significant difference across a wide range of hydration indicators compared to the consumption of equal amounts of water,” Killer said.

She and her colleagues noted that public health recommendations to exclude caffeinated beverages from daily fluid needs or to drink a glass of water for every cup of coffee or tea consumed “should be updated to reflect [our] findings.”

Folate-Deficient Diet in Male Mice Associated With Birth Defects in Offspring

Paternal folate deficiency in mice may cause birth defects in offspring due to epigenetic changes in sperm. Image: www.genome.gov

Paternal folate deficiency in mice may cause birth defects in offspring due to epigenetic changes in sperm. Image: http://www.genome.gov

It has long been known that infants born to women who are deficient in folate, one of the B vitamins, are more likely to develop neural tube defects during gestation. Now researchers are investigating whether paternal folate deficiency might have similar harmful effects on offspring and have found that this may be the case, at least in mice.

In a new study published this week in Nature Communications, researchers from McGill University in Montreal studied more than 100 male mice, giving half of them a folate-sufficient diet (2 mg/kg) and half of them a folate-deficient diet (0.3 mg/kg), starting in utero and continuing throughout life. The folate-deficient and folate-sufficient mice showed no differences in physical development and appearance (including testes development). Sperm appearance and sperm counts in the two groups were also the same.

However, when the researchers then mated these male mice with a group of folate-sufficient female mice, they found significant differences in the next generation of mice. Fetuses fathered by folate-deficient mice had a 27% rate of gross anatomical abnormalities compared with 3% in those fathered by folate-sufficient mice. These abnormalities included both craniofacial and limb defects.

These effects are likely due to folate’s involvement in a chemical process called DNA methylation, the addition of chemical tags to DNA that affect how the DNA is read by the cell. In both humans and animals, all genetic information is contained within DNA sequences that make up a genome. When DNA is modified by methylation and other similar processes, the product is referred to as an epigenome. Although one’s genome is static throughout life, one’s epigenome is highly dynamic and depends on many environmental (including dietary) factors. Furthermore, just as with genetic information, epigenetic information can be passed on to offspring.

Thus, the researchers hypothesized that the folate-deficient male mice had epigenetic changes in their sperm that were passed on to their offspring. Indeed, epigenetic analysis revealed that the 2 groups of mouse fathers had different patterns of DNA methylation in their sperm. Furthermore, an analysis of the 2 groups of subsequent fetuses found that there were differences between the groups in how 380 genes were expressed, suggesting an inherited effect of epigenetic modification. Most of these genes played important roles in development.

Of course, the results of this study must be interpreted with caution. Future studies will be necessary to further validate these results before any conclusions can be made about implications for human development.

Long-Awaited Prevention and Treatment Guidelines for Heart Disease Published

Four new guidelines give primary care physicians direction as they help their patients reduce their risk of developing heart disease. (Image: JAMA, ©AMA)

Four new guidelines give primary care physicians direction as they help their patients reduce their risk of developing heart disease. (Image: JAMA, ©AMA)

Much-anticipated national guidelines for reducing most risk factors associated with cardiovascular disease have finally been released—with one exception. Updated guidelines for addressing hypertension, which had been expected to be available earlier this year, are not yet available.

The released guidelines focus on healthy lifestyles, atherosclerotic cardiovascular risk assessment, blood cholesterol management, and obesity.

The healthy lifestyles and risk assessment guidelines are new. The cholesterol management guideline is the first update since 2004. The obesity guideline is the first update of the original document, published in 1998.

Each guideline was created by expert panels convened by the National Heart, Lung, and Blood Institute, which handed over governance, management, and publication of the guidelines last June to the Obesity Society (for the obesity guideline) and to the American Heart Association and the American College of Cardiology along with the Obesity Society for the others.

Guideline for a Healthy Lifestyle
The healthy lifestyle guideline stresses eating a generally heart-healthy diet and engaging in physical activity as key elements for preventing heart attacks, strokes, and other cardiovascular diseases. The guideline’s recommendation on diet doesn’t endorse any specific eating plan, such as the Mediterranean diet; instead, it calls for primary care physicians to develop heart-healthy dietary plans based on the individual patient’s caloric requirements and personal and cultural food preferences, with additional tweaks to account for other medical conditions, such as diabetes.

The healthy lifestyle guideline also calls for a reduction in salt (sodium) consumption but doesn’t endorse a target level, such as limiting sodium intake to 1500 mg/d as advocated by the American Heart Association and others. Regarding physical activity, the guideline advises moderate or vigorous aerobic exercise, such as brisk walking, for an average of 40 minutes 3 or 4 times a week.

Guideline for Cardiovascular Risk Assessment
Previously, cardiovascular risk assessment focused only on coronary heart disease, but the new guideline includes stroke. This is intended to improve overall cardiovascular risk assessment, particularly for women and blacks, who are at much greater risk for stroke then white men.

The guideline promotes risk assessment methods for atherosclerosis-related risk factors that are easily ascertained by a primary care physician, such as age, cholesterol levels, blood pressure, smoking, and diabetes.

Cholesterol Guideline
The cholesterol guideline emphasized reducing low-density lipoprotein cholesterol (LDL-C), the “bad” cholesterol, but doesn’t set a specific target. Instead, the guideline authors recommended moderate- or high-intensity statin therapy for 4 groups:

• Patients with cardiovascular disease
• Patients with an LDL-C level of 190 mg/dL or higher
• Patients with type 2 diabetes who are between 40 and 75 years of age
• Patients with an estimated 10-year risk of cardiovascular disease of 7.5% or higher who are between 40 and 75 years of age

The 10-year risk threshold is a lower percentage than currently used and could lead to a doubling of statin use in the adult US population, from 15% to about 30%.

Guideline for Addressing Obesity
The obesity guideline recommends weight reduction— with a goal of losing 5% to 10% of one’s body weight within 6 months—through a nonspecific reduced-calorie diet, increased physical activity, and adoption of behavioral strategies introduced by a trained professional, who should meet in person with the patient 2 or 3 times a month for 6 months.

The guideline also said that bariatric surgery may provide significant health benefits for patients with a body mass index (BMI) of 40 or higher or a BMI of 35 or higher along with 2 other cardiovascular risk factors.

What About the Hypertension Guideline?
Not included in the rollout of the 4 guidelines was the hypertension guideline, which hasn’t been updated since 2003 and had been expected to be ready for release this summer. American Heart Association President Mariell Jessup, MD, said at a press conference last week that she wasn’t sure when the hypertension guideline would be published but that like the guidelines released today, it will be based on a similar approach, performed by an expert panel.