30 December 2014

A pill for the fat and lazy

White and brown

Alexandra Bruter, <url>

Scientists from Harvard University (see the press release A pill to shed fat? – VM) together with employees of the pharmaceutical giant Roche published an article in Nature Cell Biology on how to turn white fat into brown (White-to-brown metabolic conversion of human adipocytes by JAK inhibition).

Recently, we have repeatedly written about medical methods of weight loss and treatment of overweight-related type II diabetes mellitus. Although the problem seems simple, all you need is to eat less and move more, but the obesity epidemic gaining momentum in developed countries indicates that this is the simplest and wrong solution that every problem has.

In medicine, there is such a concept, which in Russian is called the transliterated English word compliance - compliance. Usually this word is translated as "consent". This term is about the ratio of what is prescribed by the doctor and what is performed by the patient. Even when the doctor prescribes just pills, which, for example, should be taken three times a day after meals, it turns out that some patients took twice a day, some before meals, some instead of meals, some not every day, and another part replaced the pills prescribed to them with pills prescribed to their friends with similar symptoms.

Compliance can be studied by two methods: by the stories of patients and by assessing the concentration of drugs or their metabolites in the blood. Needless to say, the second method gives an even smaller percentage of properly treated patients than the first, although the first gives deplorable results. The numbers given are amazing. Studies show that hypotensive (from hypertension) drugs are incorrectly taken by 93% of Americans and 70% of Englishmen. Approximately 50% of patients take 80% or more of the prescribed medications. Similar numbers are given for insulin-dependent patients, but for them it is a matter of, if not life and death, then the ordinary life of a healthy person and a rather unpleasant life with the prospect of kidney failure, neuropathies and diabetic foot up to dialysis and amputation of limbs.

The situation with compliance is even worse when the patient must not just take medications, but perform complex manipulations that take a lot of time. For example, perform physical exercises and choose steamed vegetables from a sausage sandwich and steamed vegetables, which also need to be cooked. Therefore, the advice "eat less and move more", of course, can help each individual, but it cannot solve the problem facing the health care system as a whole. The normal healthcare system is not interested in hanging labels like "lazy fat pig", but is interested in finding a means to reduce the cost of treating obesity-related cardiovascular diseases, diabetes, etc., and it's great if it's medicated.

A promising direction in the search for such a remedy is the search for a way to turn ordinary white fat into brown. These two types of cells are very similar in origin to each other, and presumably there should be a simple way to turn one into the other, but they also have fundamental differences that are important for therapy.

In the cells of white fat, excess energy is stored in the form of triglycerides. In addition, white fat cells have hormonal activity, for example, they secrete the hormone leptin into the bloodstream, which regulates the feeling of satiety. Brown fat cells (it owes its brown color to the abundance of mitochondria), although similar to white cells, perform a different, almost opposite function. They work as heaters. The protein thermogenin is present in the mitochondrial membrane in brown fat cells. This protein arranges a kind of "short circuit" for the protons of the respiratory chain – their energy is not converted, as in ordinary mitochondria, into ATP, but simply turns into heat when a proton passes through a thermogenin molecule. The protein thermogenin is activated by fatty acids, which are formed during the breakdown of triglycerides, the same "fat". Therefore, when the body thinks it needs to warm up, it sends a command to the brown cells to "digest" fat through a chain of signals.

In addition to the release of heat, the activation of brown fat leads to a decrease in the concentration of triglycerides in the blood, increased sensitivity to insulin (reduced sensitivity is characteristic of type 2 diabetes) and prevents obesity. In some cases, browning of white fat occurs. For example, when adapting to a colder climate or with additional stimulation of receptors that activate thermogenin. It turned out that a person in the process of browning fat also has a weight loss. This strengthened the authors of the work in the idea that a molecule that turns white fat into brown will contribute to weight loss.

They started by developing a system for screening candidate molecules. The system was based on measuring the amount of matrix RNA of the protein thermogenin. Using this system, the authors tested 867 molecules for the ability to convert white fat into brown. One of them (R406) turned out to be particularly promising. This molecule inhibited the JAK3 enzyme.

Here and below are diagrams from an article in Nature Cell Biology – VM

Until now, almost nothing was known about the role of JAK3 in the transformation of two types of adipose tissue into each other or in thermogenesis, it was only known that it plays a role in the early stages of adipocyte formation. Its inhibitor, however, quite successfully coped with the transformation of some cells into others, even at the morphological level.

Portal "Eternal youth" http://vechnayamolodost.ru30.12.2014

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