All Posts tagged regulation

Obesity leads to Vitamin D deficiency

People who weigh more have lower circulating levels of Vitamin D according to recent research conducted at the Rikshospitalet-Radiumhospitalet Medical Center in Oslo, Norway and published in the Journal of Nutrition. Lead researcher, Zoya Lagunova, MD and her colleagues measured the serum levels of Vitamin D and 1,25(OH)2D in 1,779 patients at a Medical and Metabolic Lifestyle Management Clinic in Oslo, Norway. The associations among 1,25(OH)(2)D, serum 25-hydroxyvitamin D [25(OH)D], and body composition were analyzed. Lagunova noted that generally people with higher BMI had lower levels of Vitamin D. Age, season, and gender were also found to influence serum 1,25(OH)(2)D.

Vitamin D is not a true vitamin, but rather a vitamin-steroid thought to play a key role in the prevention of cancer, cardiovascular disease, diabetes, multiple sclerosis and other diseases. It is likely not coincidental that obesity is also a risk factor for many of these diseases. Vitamin D is vital to the regulation of calcium. Studies have shown that calcium deficiency increases the production of synthase, an enzyme that converts calories into fat. It has been shown that calcium deficiency can increase synthase production by up to 500 percent. Vitamin D has also been shown to play a role in the regulation of blood sugar levels; proper blood sugar regulation is vital to the maintenance of a healthy weight. Vitamin D is produced from sunlight and converted into various metabolites. It is stored in fat tissue. According to Lagunova, obese people may take in as much Vitamin D as other people; however, because it is stored in fat it may be less available. This may result in lower circulating levels of Vitamin D.

A previous study conducted by Shalamar Sibley, MD, MPH, an assistant professor of medicine at the University of Minnesota, showed that subjects who have higher levels of Vitamin D at the start of a weight loss diet lose more weight than those with lower levels. The study measured Vitamin D levels of 38 overweight men and women both before and after following an 11-week calorie-restricted diet. Vitamin D levels at the start of diet was an accurate predictor of weight loss…those with higher levels of Vitamin D lost more weight. It was found that for every nanogram increase in Vitamin D precursor, there was an 1/2 pound increase in weight loss.

Seventy-five percent or more of Americans, teenage and older, are Vitamin D deficient according to a recent study published in the Archives of Internal Medicine. According to the Gallup-Healthways Well-Being Index, 26.5% of American are obese. More research needs to be conducted into the exact role Vitamin D plays in obesity and weight loss and the possibility of increased Vitamin D consumption (through the form of supplementation and/or increased sun exposure) being a key factor to achieving a healthy weight.

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Thirty years ago Maria de Sousa, then at the beginning of her career, noticed that lymphocytes were attracted to places with surplus of iron. This, together with

1- the fact that the vertebrate immune system (IS) was incredibly more complex that those of its ancestors (and evolution rarely increases complexity, which is energetically costly, unless something is gained)

2- the IS unique capacity to reach everywhere in the body

led her to a revolutionary new idea – could this new complexity be evolutionary sound, because it allowed the IS to perform some important new function, maybe protecting the body against iron toxicity?

In fact iron, although an essential element for most life forms, can also be toxic to these same organisms when free (not attached to proteins). This means that in this form it needs to be “watched” and regulated around the clock. In vertebrates, this is done through hepcidin, a liver protein that “moves” iron between cells and plasma according to the body needs (or potential dangers). The problem is that the hepcidin liver cells have limited mobility so a complementary far reaching iron control system was needed. Lymphocytes, with their unique capacity to move throughout the body were the perfect candidates and since 1978, de Sousa and her group have been chasing this idea.

Much of their work has been done on hemochromatosis – a disease where there are problems in the absorption of iron through the digestive track leading to too much iron in the organism and to its toxic accumulation in the organs.

From this work we know now that hemochromatosis patients also have a defective IS, and more, that their iron overload levels correlate with their lymphocyte deficiency – the less lymphocytes they have the more severe the disease. Work in animal models with iron overload problems or instead, with lymphocyte deficiencies have again found links between excess of iron in the body and deficient IS further supporting de Sousa's “immuno-iron idea”.

And meanwhile, human lymphocytes were shown to produce several proteins crucial for the regulation of iron levels – ferritin, which acts as the body storage of iron (so holding to it when there is too much in the body or releasing it when there is deficiency) and ferroportin, which is the cells' iron “exit door” (again releasing or retaining iron as necessary) . The fact that lymphocytes had both proteins gave them the potential to be a “mobile” and easily “mobilizable” iron-storage compartment, characteristics perfect for an important role in iron homeostasis.

Nevertheless, the exact mechanism how this could happen remained elusive

But hepcidin, the central piece of iron regulation, is known to be also an important player in the immune response what has raised the possibility that it could be in it the clue to this problem. In fact, during infection hepcidin shuts down the “door” through which iron leaves the cell (ferroportin) reducing iron availability in the plasma and thus helping to control infection – as bacteria need iron to divide. And now several studies have shown that hepcidin is produced by a variety of cells involved in the immune response. Finally, last year, a study suggested, for the first time, that lymphocytes were also capable of producing the protein putting the possibility that hepcidin could actually be “the missing link” of de Sousa's theory.

To clarify this hypothesis Jorge Pinto, Maria de Sousa and colleagues at the Institute for Molecular and Cell Biology (IBMC) of Porto University looked at hepcidin production in human lymphocytes in situations of toxic iron concentrations or immune activation, as de Sousa's theory proposed that lymphocytes could play a role in both situations. They found that hepcidin not only was produced by all classes of lymphocytes, but also that its production increased both in the presence of high quantities of iron, and when lymphocytes were activated, backing de Sousa's proposals.

Pinto explains: “We show, for the first time, that lymphocytes can “feel” the toxic levels of iron in circulation and respond by increasing their own capacity to retain it within, restoring “normality”. The same mechanism is seen being used in situations of (iron) demand, such as when the cells are activated by the occurrence of an infection and need to divide.”

They also found something else totally unexpected – that hepcidin was involved in this second mechanism, suggesting an even closer dependence between the two systems than de Sousa had thought.

To Hal Drakesmith, a researcher at the University of Oxford working on the possibility of manipulating iron transport as a way to combat infections such as HIV, malaria and Hepatitis C these results raise particularly interesting questions as he explains “This seems to suggest that control of iron metabolism may be an integral component of lymphocyte immunity. Withholding iron from pathogens is an accepted part of our defence against infection, but a role for lymphocytes in controlling iron transport has not been proposed before.

“Crucially – says Pinto – we still believe that the main regulator of systemic iron levels is the liver but not only are lymphocytes (and not liver cells) able to sense toxic forms of iron, but they are also able to travel and be activated in specific places where the pathogens accumulate helping to control infection. “

These results are a major step to understand the link between the IS and iron and, if confirmed in live organisms –all this work was done on human cells in the laboratory – can be the beginning of a totally different view of what the immune system is and how to approach immunologic problems.

As Hal Drakesmith says “the paper describes several new findings which are highly likely to be of interest and importance to the iron and immunity fields of research” A simple example is the anaemia that usually accompanies chronic inflammatory diseases and that so far can not be clearly explained. Pinto and Sousa's results suggest that lymphocyte chronic activation, so characteristic of these diseases, by leading to hepcidin production could be part of the phenomenon as iron is an integral part of red blood cells.

Pinto, de Sousa and colleagues now plan to go back to those diseases of iron overload associated to immune abnormalities and see if hepcidin proves to be, in fact, the connection between them. Other possibility is the construction of mice without the hepcidin gene in the bone marrow – where lymphocytes develop – to analyse the changes that this could bring to both iron homeostasis and the immune response.

Whatever happens this is a strikingly interesting story with decades of persistence and believe behind it and which, I am sure, still has much to tell us.

By Catarina Amorim

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Trans Fats Interfere with Blood Flow

Trans fats are made through hydrogenation, which involves bubbling hydrogen through hot vegetable oil, changing the arrangement of double bonds in the essential fatty acids in the oil and “saturating” the “unsaturated” carbon chain with hydrogen. Because double bonds are rigid, altering them can straighten or twist fat molecules into new configurations that give the fats their special qualities, such as the lower melting point of margarine that makes it creamy at room temperature.

Kummerow, 94, has spent nearly six decades studying lipid biochemistry, and is a long-time advocate for a ban on trans fats in food.

While the body can use trans fats as a source of energy for maintenance and growth, Kummerow said, trans fats interfere with the body's ability to perform certain tasks critical to good health. Because these effects are less obvious, many researchers have missed the underlying pathologies that result from a diet that includes trans fats, he said.

Trans fats displace – and cannot replace – the essential fatty acids linoleic acid (omega-6) and linolenic acid (omega-3), which the body needs for a variety of functions, including blood flow regulation. Studies have shown that trans fats also increase low-density lipoproteins (LDLs) in the blood, a factor which some believe contributes to heart disease.

Trans fats are associated with increased inflammation in the arteries. And trans fats have been found to change the composition of cell membranes, making them more leaky to calcium. Inflammation, high LDL cholesterol and calcified arteries are the signature ingredients of atherosclerosis.

Trans fats also were shown to interfere with an enzyme that converts the essential fatty acid linoleic acid into arachidonic acid, which is needed for the production of prostacyclin (a blood-flow enhancer) and thromboxane (which regulates the formation of blood clots needed for wound healing). While some in the food oil industry believed this problem could be overcome simply by adding more linoleic acid to partially hydrogenated fats, in 2007 Kummerow's team reported that extra linoleic acid did not overcome the problem.

“Trans fats inhibited the synthesis of arachidonic acid from linoleic acid, even when there was plenty of linoleic acid available,” he said.

The new study reports that in addition to interfering with the production of arachidonic acid from linoleic acid, trans fats also reduce the amount of prostacyclin needed to keep blood flowing. Thus blood clots may more easily develop, and sudden death is possible.

According to the American Heart Association, each year more than 330,000 people in the U.S. die from coronary heart disease before reaching a hospital or while in an emergency room. Most of those deaths are the result of sudden cardiac arrest, the Heart Association reports.

“This is the first time that trans fatty acids have been shown to interfere with yet another part of the blood-flow process,” Kummerow said. This study adds another piece of evidence to a long list that points to trans fats as significant contributors to heart disease, he said.

Kummerow believes the U.S. Food and Drug Administration's new requirement (begun in 2006) that trans fats be included on food labels is inadequate and misleading. Anything less than one-half gram of trans fats per serving can be listed as zero grams, Kummerow said, so people are often getting the mistaken impression that their food is trans fat-free.

“Go to the grocery store and compare the labels on the margarines,” he said. “Some of them say zero trans fat. That's not true. Anything with partially hydrogenated oils in it contains trans fat.”

“Partially hydrogenated fats can be made trans fat-free,” Kummerow said. “The industry would be helped by an FDA ban on trans fat that would save labeling costs, medical costs and lives.”

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