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Biochemistry

Well-regulated insulin and glucose

Physical activity and unsaturated fatty acids such as omega-3 revert inflammation that unleashes obesity and diabetes

LAURA DAVIÑALAURA DAVIÑAEverybody has long known that exercising regularly and avoiding too much fatty red meat helps prevent obesity and diabetes. However, explanations as to why these recommendations worked were superficial. Now these recommendations have been finally understood: physical activity protects the region of the brain that regulates the appetite; this is the region that is attacked by saturated fats, such as those found in a rump steak. According to recent studies, some of them conducted in Brazil, the beneficial effects of physical exercise are similar to those provided by the consumption of another kind of fat. More specifically, this fat is unsaturated and is found in the omega-3 oils of cold-water fish. These findings have given rise to new possibilities of deterring obesity and diabetes, especially type 2 diabetes, in which the body produces insulin but does not use it adequately.

Part of this new information has come from a team at the Medical School of the State University of Campinas (Unicamp); the team is coordinated by endocrinologist Mário Saad. For many years, he and his team have studied the causes of organic imbalances that lead to obesity and diabetes. Last year, Lício Velloso identified the specific cause of these diseases: excessive consumption of long-chain saturated fats can generate an inflammation of the hunger-controlling neurons of the hypothalamus, located just above the brain stem (see Pesquisa FAPESP no. 156, February 2009). The inflammation keeps the hormone insulin from working properly, which makes it easier to capture glucose in the cells. The neurons of the hypothalamus lose their capacity to bind with insulin – a phenomenon called insulin resistance that causes hunger to predominate over satiety. This condition is found in obese people and in diabetics. Recently, Eduardo Ropelle has concluded that physical exercises not only burn calories – as is widely known – but also help to reduce the inflammation in the neurons of the hypothalamus and re-establish satiety.

Ropelle transformed normal mice into obese ones by feeding them a diet high in saturated fats. He then made some of the mice swim and run on a treadmill, while the other mice remained at rest. The mice that exercised intensely produced anti-inflammatory proteins known as interleukins (in this case, two types: IL-6 and IL-10), as described in detail in an article published this month in PLos Biology. These interleukins reduced the inflammation in the neurons of the hypothalamus and the insulin started functioning normally. The animals in this group started to eat less and to lose weight.

“Physical activity re-established the molecular and cellular balance of the hypothalamus,” Ropelle concluded. To check whether these two proteins actually had this effect, Ropelle applied IL-6 and IL-10 to the brains of the obese mice that had not exercised, whereupon they too lost weight. Genetically modified mice, unable to produce these two types of interleukins, continued gaining weight, even if they swam or ran. This study raises the possibility of controlling obesity and diabetes by interfering in inflammatory processes in the central nervous system, not necessarily by means of interleukins, which can weaken the body’s defense against disease-causing microorganisms.

In their search for the deeper origins of insulin resistance, Velloso and Saad concluded that saturated fats bind with the cell membrane proteins, known as TLR-4. The receptors activate the enzymes that block the action of the insulin, keeping glucose from doing its job (see Pesquisa FAPESP no. 140, October 2007). “When it is activated,” says Velloso, “the TLR-4 cell receptor activates the inflammation and cell stress that can cause neuron death. The consequence can be an imbalance in the number of neurons, if more hunger-triggering neurons die than satiating neurons.” Luckily, he adds, the omega-3 unsaturated fatty acids might have the opposite effect of the saturated fatty acids, blocking this inflammation instead of stimulating it. This classification of fatty acids results from the number of chemical double bonds between their carbon atoms; saturated fatty acids lack such double bonds, whereas unsaturated fatty acids have at least one. The type of chemical bond determines the spatial structures (saturated fatty acids are long, while unsaturated fatty acids are curved) and their properties, such as the ability to interact with different molecules of the organism.

Velloso believes that the anti-inflammatory property of omega-3 unsaturated fatty acids could be put to better use, for example, to drive changes in food composition, such as increasing the amount of the healthy fats. In the last few years, this has already helped to reduce the risk of heart attacks and other heart conditions and could also help people whose bodies deal with glucose poorly. In Brazil, 6 million people have been diagnosed with diabetes and another 6 million might not even know they are diabetic because they have not been diagnosed as such. According to recent data released by the Ministry of Health in June, nearly half of Brazil’s population is overweight or obese; the numbers rose from 43% in 2006 to 47% in 2009.

“Palmitic acid, a saturated fatty acid, activates the TLR-4 cell receptor and the inflammatory processes that lead to insulin resistance; palmitoleic acid, an unsaturated fatty acid, produces the opposite effect and diminishes resistance to insulin,” points out Rui Curi, coordinator of a research group in this field at the Biomedical Sciences Institute (ICB) at the University of São Paulo (SP). Jarlei Fiamoncini, a member of Curi’s team, conducted an experiment that clearly showed this contrast. Mice that had been put on a diet of unsaturated fatty acids from the omega-3 family (eicosapentaenoic acid/ EPA and docosahexaenoic acid/ DHA), found in cold water fish such as salmon and codfish, proved to be more sensitive to insulin, normalizing the concentration of glucose in the blood. Excess glucose in the blood can damage nerves and blood vessels.

LAURA DAVIÑAIn this experiment, in addition to normalizing glucose levels, the diet based on fish oil reduced the production of the enzymes that form fats from carbohydrates (sugars). As a result, the animals from this group gained less weight than the animals from the other group, which had been fed lard, which is high in saturated fatty acids. “Saturated fats such as lard hinder the capturing of glucose and can induce insulin resistance,”  he says. The animals from the second group were hungrier, ate more, and gained weight.

Saturated or unsaturated fats can have opposite effects on muscle cells as well. An excess of two types of saturated fatty acids – palmitic acid and stearic acid – jeopardized the functioning of  lab-grown muscle cells and hindered the action of insulin, while unsaturated oleic, linoleic, EPA, and DHA acids produced no changes in the functioning of the cells and let insulin act normally, according to studies conducted by Sandro Massao Hirabara, a professor at Cruzeiro do Sul University (Unicsul). “Omega-3 unsaturated fatty acids prevent insulin resistance induced by saturated fatty acids,”  he states, based on research currently under way.

“No wonder the Japanese and the Eskimos, who eat a lot of fish high in omega-3 unsaturated fatty acids, have a lower incidence of heart problems, obesity and diabetes in comparison to other populations,” says Curi. Therefore, it is probably a good idea to replace foods high in saturated fatty acids (soybean oil, butter, animal fat) by foods high in unsaturated fatty acids (olive oil, linseed oil or sunflower oil). Those who have already done so can move on to the next level, by substituting foods high in omega-6 unsaturated fatty acids by foods high in unsaturated omega-3 fatty acids; corn, sunflower, saffron and soybean oils contain linoleic acid, from which the other components of the omega-6 family derive. Canola and linseed oils, nuts and dark green leafy vegetables are high in alpha linoleic acid, the main component of the omega-3 family. Not all omegas – even the unsaturated ones – have the same effect on the organism. Like the Roman god Janus, fatty acids, even those of the same type, are double-faced and have opposite effects. “Omega-3 unsaturated fatty acids reduce the inflammation that can lead to insulin resistance, whereas omega-6 unsaturated fatty acids can do the opposite”  says Curi, referring to the Janus effect.

Fatty acids can help diabetics deal with one of the problems that affect them: the difficulty in wound healing, which leads even slight injuries to turn into chronic ones, says Elaine Hatanaka, from Unicsul. Her team, together with colleagues from USP, studied the action of three fatty acids – oleic, linoleic and linolenic acids – on induced injuries in rats. The three compounds speeded up the formation of scar tissue. As an initial effect, the team stimulated the migration of neutrofiles – one type of blood cell – to the injury. The neutrofiles, in turn, produced more proteins called cytokines, which facilitate communication between cells. The cytokines helped the injuries heal, as described in an article published in Cell Biochemistry and Function.

The effect of those fatty acids (yet another sign of the Janus effect?) is uneven. “The effect of fatty acids can be different, depending on the type of cell,” says Elaine. In addition, in a second stage in the process of wound healing, the same fatty acids acted inversely: they made the levels of cells and communicating proteins –  which had been momentarily high –  go back to normal. “The fatty acids modulated the inflammatory response during the wound healing process, initially expanding the effect and number of neutrofiles and citokynes (the proteins that facilitate cell interaction) and then reducing them to normal levels,” Elaine comments. The studies in this field explain the scar tissue effect of plant oils such as copaiba oil, which has high leic and linoleic acid content, and the ancient habit in traditional Chinese medicine of treating injuries with the extract of cricket glands, which is high in linoleic acid, as we now know.

A study on mice conducted at the Federal University of Paraná (UFPR) in Curitiba strengthened the possibility of using fatty acids -especially unsaturated ones – against cancer. Luiz Claudio Fernandes and his team found that the aggressive Walker tumor grew much less in animals fed on a diet high in EPA and DHA unsaturated fatty acids than in animals that were not given an extra dose of lipids. According to Fernandes, in the animals from the first group, the production of prostaglandin-3, a compound derived from fatty acids that puts a brake on cell multiplication, increased and the tumor grew less. In the other group, prostaglandin-2, which triggers the multiplication of normal and tumor cells, rose. Fernandes also noted less of one of the effects of cancer, cachexy, a condition characterized by loss of appetite and general physical wasting due to the high consumption of glucose by the tumors, among the mice treated with omega-3 lipids.

LAURA DAVIÑALAURA DAVIÑAHe believes that the human body might have similar reactions. “When we place human tumor cells from the colon, lung, or prostate in a culture with omega-3, the tumor’s proliferation rate drops,” he says. “There are still few tests conducted on humans, but from what we have seen so far, the undesirable side effects of fatty acids are minimal: flatulence or diarrhea.” At UFPR, the group coordinated by Anete Curte Ferraz found that omega-3 helps reduce depression in people with Parkinson’s disease or severe depression, according to a double-blind study with 31 participants published in 2008 in the Journal of Affective Disorders. In another study, researchers from the Federal University of São Paulo (Unifesp), from USP in Ribeirão Preto and from the University of Mogi das Cruzes (UMC) concluded that omega-3 can protect the neurons of the central nervous system and reduce the frequency of epileptic crises (see Pesquisa FAPESP no. 169, March 2010). In Finland, a study on 33 thousand women indicated another possible application of omega-3 and omega-6 unsaturated fatty acids, complemented with Vitamin D: the reduction of schizophrenics’ psychotic episodes.

These studies underscore the versatility of fatty acids. However, one should not rush to the drugstore and buy fatty acids in the belief that they will make one as healthy as a child. The benefits depend on the type of fatty acids and on the dose. “Even unsaturated fatty acids like EPA and DHA in high doses, as found in parenteral diets [intravenous feeding of people that cannot feed themselves orally] can be toxic for blood cells,” says Maria Fernanda Cury Boaventura, from Unicsul. In tests on healthy volunteers and patients in hospitals, Maria Fernanda and other researchers from USP found that excess levels of fatty acids in the blood – as occurs in healthy people when they are fasting or in obese or diabetic people, and not only in patients who are in hospital and have just received parenteral nutrition – can cause a small reduction in the number of  lymphocytes, a type of defense cell.

The work done so far may motivate healthcare professionals to look for better treatment for patients under their care. “Some hospitals already put patients on diets based on fish oil, but not to a great extent,” says Maria Fernanda. “We have to specify the doses and the composition of the diets according to the patient. Parenteral nutrition based on soybean oil – the most common nutrition of this kind in the world – can help weaken the body’s defense mechanisms – in other words, it can act as an immunosuppressant; this can be harmful to most hospitalized patients, but could be prescribed for transplant patients, for example.” Curi adds: “We still don’t know how much fatty acid each kind of diet should contain, but we already know which fatty acids should be included and which should not be included in excess. The important thing is how the combinations are prepared.” Pure compounds are still very expensive, which is another reason for preferring combinations.

The Projects
1.
Study of the action mechanisms of fatty acids in leucocytes (nº 2004/12137-1); Type Thematic Project; Coordinator Rui Curi – ICB/USP; Investment R$ 996,865.44 (FAPESP).
2. Pro-inflammatory mechanisms involved in the hypothalamic control of hunger and thermogenesis (nº 2004/09789-7); Type Thematic Project; Coordinator Lício Velloso – Unicamp; Investment R$ 1,090,428.79 (FAPESP).

Scientific Articles
HIRABARA, S. et al. Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cellsJournal of Cellular Physiology. v. 222, n. 1, p. 187-94. 2009.
PEREIRA, L. M. et al. Effect of oleic and linoleic acids on the inflammatory phase of wound healing in ratsCell Biochemistry and Function (forthcoming).
ROPELLE, E. R. et al. IL-6 and IL-10 anti-inflammatory activity links exercise to hypothalamic insulin and leptin  sensitivity through IKK and ER stress inhibitionPLoS Biology (forthcoming).

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