March 2008, HHMI – A team led by Howard Hughes Medical Institute (HHMI) researchers has identified a network of hundreds of genes that keep embryonic stem cells in their characteristic malleable state, able to develop into any cell type when the time comes. The finding, based on studies of mouse cells, provides valuable insight into the way stem cells function, and could help researchers find ways to reprogram adult cells for therapeutic use.

Led by Stuart Orkin, an HHMI investigator at Children’s Hospital Boston, the team published its findings in the March 21, 2008, issue of the journal Cell.

“We’re asking: ‘Well, we’ve got all these proteins—what are the genes they likely regulate?’”
Stuart H. Orkin

Embryonic stem cells are the ultimate in indecision. Precursors of all the specialized cells of the body, embryonic stem cells exist in an undefined form until the time comes to head down the path toward nerve, organ, or muscle. Embryonic stem cells are distinct from other cells in two ways. First, they are pluripotent—they have the ability to develop into any cell type. Second, they are perpetually self-renewing, meaning that unlike other cells they do not die after a set number of divisions.

For years, researchers have sought to decipher the genetics behind these unique characteristics. In 2006, Orkin’s team reported in the journal Nature that a set proteins that physically associate with one another regulates gene activity critical for maintaining cells in the embryonic stem-like state. These proteins, called transcription factors, bind to regulatory regions of DNA associated with specific genes and influence the genes’ activity by encouraging or restricting their transcription (the first step in making a protein).

According to Orkin, the new study is a sequel to that Nature paper. “We’re asking: `Well, we’ve got all these proteins—what are the genes they likely regulate?’”

To find out, the team tagged a set of nine critical proteins with “molecular hooks” that made it possible to fish out the proteins attached to their target genes. Together, the proteins bound to roughly 6,500 genes that fell into two groups: those that the proteins kept switched off in the stem cells, and those that they switched on. However, it wasn’t a simple matter of each gene being turned on or off by one transcription factor.

Instead, Orkin explained, “one class is genes that are targeted by many of the nine proteins we tested—even as many as six, seven, or eight. These genes tend to be on in embryonic stem cells, and off when the cells differentiate.” Genes that were turned off in the embryonic stem cells, on the other hand, were bound by only one or two of the transcription factors.

According to Orkin, “This is the first time we’ve had a sense that one could distinguish these classes.” And, he said, the identity of the genes fit with the scientists’ expectations of functions that need to be regulated to maintain the stem cell state. “They have to promote self renewal,” he said, “but at the same time they have to block differentiation. The two classes we see seem to more or less fit into those functions.”

Orkin said that the findings represent a “catalog of the genes bound by these factors,” which he hopes will be useful in future studies. According to Orkin, there has been a recent explosion of interest in reprogramming skin or other developed cells to act like stem cells, with the ultimate goal of treating disease. But currently, he said, the process is still essentially a “black box.” “You add genes, and the cells reprogram,” he said. “What happens in between?

“This kind of work provides the materials to get a better understanding of that process,” said Orkin. “The goal is to be able to manipulate cells in a very directed way.”

A new study has implicated meat, fried food and, surprisingly, diet soda in the development of metabolic syndrome. More research will now be needed to confirm and explain these intriguing findings.

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Metabolic syndrome is a cluster of conditions that increases the risk for heart disease and stroke. Doctors consider someone to have metabolic syndrome when they have 3 or more risk factors, which include elevated blood pressure, low HDL (good cholesterol) levels and diabetes or pre-diabetes.

Various aspects of diet have been linked to metabolic syndrome in previous studies, but the diet’s role in the syndrome’s genesis isn’t well understood. Dr. Lyn M. Steffen at the University of Minnesota’s School of Public Health and her colleagues set out to take a broad look at the relationship between metabolic syndrome and dietary intake. They used data from 9,514 middle-aged adults enrolled in the multicenter Atherosclerosis Risk in Communities (ARIC) study. The study was initiated by NIH’s National Heart, Lung and Blood Institute (NHLBI) to investigate the factors that contribute to atherosclerosis (the buildup of cholesterol and fat in the walls of arteries) and the incidence of cardiovascular diseases.

ARIC assessed dietary intake, both at the beginning of the study and 6 years later, by using a 66-item food frequency questionnaire. By 9 years later, nearly 40% of the study’s participants had developed metabolic syndrome. The new analysis of ARIC data appeared in the February 19, 2008, issue of Circulation.

The study found that a Western dietary pattern—characterized by high intakes of refined grains, processed meat, fried foods and red meat—was associated with a greater risk of developing metabolic syndrome. Upon closer analysis, the researchers found that those who ate the most meat were more likely to develop metabolic syndrome. In particular, hamburgers, hot dogs and processed meats were each associated with higher rates of metabolic syndrome. Fried foods were also associated with an increased risk.

The researchers didn’t find any association, positive or negative, between metabolic syndrome and whole grains, refined grains, nuts, coffee or fruits and vegetables. On the other hand, they found that those who ate more dairy were less likely to develop metabolic syndrome.

Strikingly, diet soda was strongly associated with an increased risk for metabolic syndrome, although sweetened beverages such as juices and regular soda were not. Other recent studies have found links between diet soda and metabolic syndrome as well as weight gain. As a possible explanation, findings in rodents suggest that artificial sweeteners may lead to increased intake because they may interfere with the body’s ability to properly assess how many calories are in foods.

These findings, however intriguing, are not conclusive. Whole grains have been found in previous studies to lower the risk of metabolic syndrome, but this study didn’t. Certain foods in themselves may not play a role in causing metabolic syndrome, but rather may serve as markers for other behaviors that do lead to metabolic syndrome. More research into what causes metabolic syndrome will hopefully clear up the confusion.

—by Harrison Wein, Ph.D.

What Is Metabolic Syndrome?

Metabolic syndrome is the name for a group of risk factors linked to overweight and obesity that increase your chance for heart disease and other health problems such as diabetes and stroke. The term “metabolic” refers to the biochemical processes involved in the body’s normal functioning. Risk factors are behaviors or conditions that increase your chance of getting a disease. In this article, “heart disease” refers to coronary heart disease.

The five conditions listed below are metabolic risk factors for heart disease. A person can develop any one of these risk factors by itself, but they tend to occur together. Metabolic syndrome is diagnosed when a person has at least three of these heart disease risk factors:

  • A large waistline. This is also called abdominal obesity or “having an apple shape.” Excess fat in the abdominal area is a greater risk factor for heart disease than excess fat in other parts of the body, such as on the hips.
  • A higher than normal triglyceride level in the blood (or you’re on medicine to treat high triglycerides). Triglycerides are a type of fat found in the blood.
  • A lower than normal level of HDL cholesterol (high-density lipoprotein cholesterol) in the blood (or you’re on medicine to treat low HDL). HDL is considered “good” cholesterol because it lowers your chances of heart disease. Low levels of HDL increase your chances of heart disease.
  • Higher than normal blood pressure (or you’re on medicine to treat high blood pressure). Blood pressure is recorded as two numbers, usually written one on top of or before the other, such as 120/80. The top or first number, called the systolic blood pressure, measures the pressure in the bloodstream when your heart beats. The bottom or second number, called the diastolic blood pressure, measures the pressure in your bloodstream between heartbeats when the heart is relaxed.
  • Higher than normal fasting blood sugar (glucose) (or you’re on medicine to treat high blood sugar). Mildly high blood sugar can be an early warning sign of diabetes.
  • The more of these risk factors you have, the greater your chance of developing heart disease, diabetes, or a stroke. In general, a person with metabolic syndrome is twice as likely to develop heart disease and five times as likely to develop diabetes as someone without metabolic syndrome.

Other risk factors aside from those of the metabolic syndrome also increase your risk for heart disease. A high level of LDL cholesterol (low-density lipoprotein cholesterol; considered “bad” cholesterol) and smoking, for example, are key risk factors for heart disease, but they aren’t components of metabolic syndrome. Even a single risk factor raises your risk for heart disease, and every risk factor should be lowered to reduce the risk.

The chance of developing metabolic syndrome is closely linked to being overweight or obese and to a lack of physical activity. Another cause is insulin resistance. Insulin resistance is a condition in which the body can’t use its insulin properly. Insulin is a hormone the body uses to help change blood sugar into energy. Insulin resistance can lead to high blood sugar levels and is closely linked with being overweight or obese.

Genetics (ethnicity and family history) and older age are other important underlying causes of metabolic syndrome.

Outlook

About 47 million adults in the United States (almost 25 percent) have metabolic syndrome, and the numbers continue to grow. The increasing number of people with this condition is connected to the rise in obesity rates among adults. In the future, metabolic syndrome may overtake smoking as the leading risk factor for heart disease.

It’s possible to prevent or delay metabolic syndrome, mainly with lifestyle changes. A healthy lifestyle is a lifelong commitment. Successfully controlling metabolic syndrome takes a long-term effort and teamwork with your health care providers.

Other Names For Metabolic Syndrome

  • Syndrome X
  • Insulin resistance syndrome
  • Dysmetabolic syndrome
  • Hypertriglyceridemic waist
  • Obesity syndrome