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Extra energy under the skin

Component of bile activates chain of chemical reactions in the muscles that prevents obesity

MIGUEL BOYAYANAt the end of 1998, a few months after being installed as visiting professor in one of the laboratories of Harvard University, United States, physician Antonio Bianco found in muscles of primates, including human beings, the same protein that he had worked on in rats over 15 years at the University of São Paulo (USP). It was D2, as the enzyme is called that activates the main hormone produced by the thyroid gland, and, from that point, speeds up the reactions that increase the intake of oxygen or, in practical terms, the release of heat.

Seven years later, now occupying the position of research director of the thyroid laboratory of the Brigham and Women’s Hospital in Boston, affiliated to Harvard University, Bianco discovered two mechanisms by which the organism can regulate the production and activity of this protein. These discoveries, published in two recent articles in Nature and in Nature Cell Biology, may lead to new therapeutic approaches to fight obesity, frequently associated with type 2 diabetes – a serious problem for about 300 million persons, and the cause of death of 3 million individuals a year. To the extent that they act as a basis for new medicines, these findings may also contribute towards the treatment of other hundreds of millions of persons who suffer from thyroid disorders.

One of the recently discovered mechanisms that induce the production of D2 puts bile into the picture, a greenish liquid produced daily during digestion that first of all attracted the interest of the philosophers, starting with the Greeks. One of them, Hippocrates, divided the body fluids into four humors – black bile, yellow bile, phlegm and blood -, corresponding to four universal elements – earth, water, fire and air – and to the seasons of the year.

For Hippocrates, diseases resulted from an imbalance between these four humors. Despite this popularity, the biliary salts, the main component of bile, did not earn much attention for centuries. It used to be admitted that they took part exclusively in the absorption of lipids – or fats – and in the elimination of cholesterol. Only three decades ago was it discovered that they could have other tasks in the organism. Indeed, it was shown that they act they act in other chemical reactions – and not just in the liver, where they are produced, or in the intestine, where they act in the absorption of fats, but also in other parts of the body. Slowly, they have ceased to by merely an emulsifying agent – a kind of detergent – of fats, and gained the status of multitask hormones.

In a study published in January 2006 in Nature, Bianco and researchers from institutes in France and Japan describe the results of an experiment that shows the effects in mice of a diet rich in biliary salts. One of them is an increase in the activity of the D2 enzyme in the brown adipose tissue – a tissue specialized in the production of heat in small rodents – and, as has also been demonstrated, in human skeletal muscular tissue. This phenomenon was not seen in the rodents, in which the action of the gene that leads to the production of the D2 enzyme was blocked.  After being activated by the biliary salts, the D2 accelerates the cellular metabolism, with a greater spending of energy, preventing obesity and type 2 diabetes, caused by a deficiency in the activity of the insulin.

The researchers concluded that the biliary acids bind themselves to specific molecules, the receptors ? on the surface of fat cells. In response, there is an increase in the intracellular production of signaling molecules that activate the gene of the D2, an abbreviation that stands for type 2 iodothyronine deiodinase. This is only half of the way. In turn, the D2 converts the thyroxine, or T4, a prohormone of the thyroid, into the T3 hormone. It is the T3 that starts a series of chemical reactions that increase the metabolic activity of the muscles and make them work like a car?s radiator, releasing heat.

“This is a very selective mechanism, which only works in cells like those of the skeletal muscles, which contain at the same time the specific receptors of the biliary acids and the D2”, Bianco says. “As a result, the spending of energy increases, without modifying the levels of thyroidal hormones in the circulation or the metabolic processes in other cells.” According to him, these studies demonstrate the essential role of the biliary acids and of the hormones of the thyroid in the regulation of the organism, also called homeostasis, “besides showing how sophisticated the medicine of the ancient Greek already was”.

If this first mechanism producing the D2 implies the activation of the gene of this enzyme, the second mechanism – described by Bianco in July last year in an article in Nature Cell Biology – depends essentially on a protein known by the abbreviation WSB1, which, as he saw, controls the D2’s time of life. “After recognizing and binding itself to the D2, the WSB1 assists in the binding of another protein, ubiquitin, to the D2”, Bianco explains. The structure of ubiquitin had already been characterized three decades ago, but its function was clarified only recently. In 2004, Aaron Ciechanover and Avram Hershko, both from the Technion-Israel Institute of Technology, shared the Nobel Prize in Chemistry with Irwin Rose, from the University of California, United States, for having identified for degrading proteins, which are destroyed after binding themselves with the ubiquitin.

It is not only the D2 that is marked to die after getting an ubiquitin – most cells produced by the cells have the same destiny. “One very important characteristic of this mechanism is that it is adjustable and highly specific, since it requires the interaction of a ligase, as with the WSB1, which make the link between the ubiquitin and the protein that is being marked for degradation”, Bianco explains. The ubiquitin deactivates the D2 and makes it be destroyed in a few minutes by other enzymes. On the other hand, a D2 to which no ubiquitin has been bound remains in the cell for many hours.

Bianco also showed how another protein, the VDU1, recognizes, binds itself to and saves the D2 from degradation, removing the ubiquitin from it. “It’s like a switch”, he compares. Examining this on-off mechanism, he concluded that by inhibiting the action of the WSB1 the D2 could remain active for more time – normally, its half life, as is called the time in which half of the quantity of molecules decays, varies from ten minutes, when connected to the ubiquitin, to about five hours.

Controlling this mechanism could not only accelerate the burning of fats. By increasing or decreasing the conversion of the T4 prohormone to the T3 hormone, it would also mean a way of helping to regulate the quantity of thyroidal hormone in circulation in the organism. The lack of T4 and, as a consequence, of T3, which characterizes hypothyroidism, causes fatigue, loss of weight and of memory, intolerance to the cold and depression or irritability, amongst other symptoms; its excess, hyperthyroidism, speeds up the heart rate, prompts trembling and causes weight loss.

In hypothyroidism, the organism tries to increase the activity of the D2, maximizing the conversion of T4 into T3. This transformation of the prohormone into active hormone is only possible because, in these circumstances, the WSB1 ceases to bind itself to the D2, maximizing the production of T3, as Bianco demonstrated by means of experiments in cell cultures and in mice. But in hyperthyroidism, the opposite occurs: the WSB1 seems to look for the D2 and, with more intensity, adds to it an ubiquitin, thus preventing even more hormone from being produced.

The search for a mate
Bianco believes that the use of this knowledge to generate new forms of medical treatment really is viable – and has now obtained in the United States the registration of a patent over the mechanism for binding the biliary acids to the receptor of the muscle cells, which activates the D2 and can be used for a treatment against diabetes and obesity. He intends to find a molecule similar to the molecule of the biliary acids, to bind it to the cell receptor and activate the D2 and the production of the T3 hormone with the minimum possible of side effects.

“Prolonged treatment with biliary salts is not recommended, because of adverse effects”, he warns. “We are in contact with pharmaceutical companies, which have proved to be very interested in licensing our patent.”

He is not the only Brazilian working in the thyroid laboratory of the hospital in Boston that is home to these researches. In the last few years, under his supervision, Rogério Ribeiro and Cyntia Curcio, postgraduate students from the Federal University of São Paulo (Unifesp), Luciane Capelo, from USP, and Miriam Ribeiro, a physiology professor from the Mackenzie Presbyterian University, have passed through there. At this moment, Marcelo Christoffolete and Beatriz Freitas, and Unifesp, and postdoctoral student Wagner Seixas da Silva, from the Federal University of Rio de Janeiro (UFRJ) are there.