{"id":219781,"date":"2016-06-29T15:13:41","date_gmt":"2016-06-29T18:13:41","guid":{"rendered":"http:\/\/revistapesquisa.fapesp.br\/en\/?p=219781"},"modified":"2016-06-29T15:13:41","modified_gmt":"2016-06-29T18:13:41","slug":"a-fat-that-fights-obesity","status":"publish","type":"post","link":"https:\/\/revistapesquisa.fapesp.br\/en\/a-fat-that-fights-obesity\/","title":{"rendered":"A fat that fights obesity"},"content":{"rendered":"
\"Salmon

L\u00c9O RAMOS<\/span>Salmon and flaxseed: foods rich in unsaturated fats such as omega-3 seem to fight brain inflammation associated with weight gainL\u00c9O RAMOS<\/span><\/p><\/div>\n

The human body\u2019s reactions to the intake of diets rich in fats are complex and characterized by aspects that are both positive and negative.\u00a0 The heart is probably the organ in which the potential risks and benefits of this dual relationship are best known.\u00a0 Some types of fatty acids tend to deposit in the body\u2019s tissues, raising blood pressure and increasing the risk of heart problems.\u00a0 This is the case with the fatty acids found in red meat, poultry and whole-milk by-products, as well as with trans fats, which are created during the process of hydrogenation of vegetable oils and used in many industrially processed foods.\u00a0 Other forms, such as unsaturated fats, seem to help maintain lower cholesterol and blood pressure levels and help keep blood vessels relatively clear.\u00a0 In the past two decades, a similarly complex relationship with the various types of fat began to be examined more closely in another vital organ \u2013 the brain.<\/p>\n

New studies have raised evidence that obesity, generally characterized by an excessive consumption of saturated and trans fats as part of an individual\u2019s eating habits, coupled with an unhealthy lifestyle, could produce chronic inflammation of the hypothalamus.\u00a0 Damage to this region that is situated at the base of the brain and functions as a nutrient sensor could lead to the death of neurons responsible for controlling the sensations of hunger and satiety as well as energy expenditure.\u00a0 Thus, the improper functioning of the circuits that regulate eating behavior\u2014the individual feels hungry after a hearty meal\u2014contribute to perpetuating weight gain.\u00a0 This is one of the harmful effects that can arise from the accumulation of saturated fats in the central nervous system.\u00a0 A recent study at the Obesity and Comorbidity Research Center (OCRC), one of the 17 Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP, indicates that the brain damage in obese animals that were fed diets rich in saturated fats could be partially reversed by consuming foods or compounds rich in another type of fat known as unsaturated fat, basically the same fats that are good for the heart.<\/p>\n

By using two different approaches, researchers at the OCRC gave obese mice unsaturated fatty acids of the omega-3 family and discovered the formation of new neurons in the hypothalamus.\u00a0 One group of rodents was fed a diet rich in omega-3 fatty acids, present in large quantities in algae, cold-water fish like salmon and tuna, and in flaxseed.\u00a0 The other group received docosahexaenoic acid (DHA), a polyunsaturated fatty acid of the omega-3 family, through direct injection into the hypothalamus.\u00a0 A third group received\u00a0 only the addition of salt solution to their diet.<\/p>\n

Eight weeks later, in the rodents given feed rich in omega-3 fatty acids and in those that received doses of DHA, the researchers verified the emergence in the hypothalamus of POMC neurons, which modulate the sensation of satiety.\u00a0 The control group presented no formation of new neurons.\u00a0 \u201cThis is the first study that shows neurogenesis in the hypothalamus induced by a food nutrient, like a diet rich in omega-3,\u201d says physician L\u00edcio Velloso of the School of Medical Sciences of the University of Campinas (FCM-Unicamp), coordinator of the center and the animal study.\u00a0 \u201cPerhaps the unsaturated fats can be a way to minimize neuron death caused by brain inflammation linked to obesity.\u201d\u00a0 The study was published in the American journal Diabetes <\/em>on October 28, 2015.<\/p>\n

Researchers are able to distinguish the new neurons– whose formation was stimulated by the diet rich in omega-3– from among those already present in the brains of rodents by using cell markers to differentiate them.\u00a0 The animals were injected with a cell proliferation marker called BrdU (bromodeoxyuridine), a synthetic nucleoside (a nitrogenous base linked to a sugar) that is an analog of thymidine, which can be combined with a fluorescent antibody. During DNA synthesis, BrdU replaces the thymidine and is incorporated into the newly generated cells.\u00a0 Thus, the compound is a useful molecular tool for ascertaining whether the birth of neurons in the brain has occurred.<\/p>\n

In the experiment conducted at the OCRC, the researchers generated images of the hypothalamic region of obese mice obtained using confocal microscopy.\u00a0 In the animals in which there was no neurogenesis, only red cells that represent the POMC neurons already present in the rodents appeared.\u00a0 In the animals that produced new neurons induced by the diet rich in DHA, green dots also appeared, indicating new nerve cells marked by the BrdU compound.\u00a0 \u201cWe evaluated other regions of the brain and saw that the neurogenesis stimulated by the omega-3 fats appears to occur mainly in certain areas of the hypothalamus,\u201d says biologist Lucas Nascimento, lead author of the study, who defended his doctoral dissertation on the topic in 2015 at Unicamp (he is currently working on a postdoctoral fellowship at the Helmholtz Zentrum, in Germany).\u00a0 The RIDC researchers also found evidence that the DHA stimulated neurogenesis by interacting with two proteins:\u00a0 the brain-derived neurotrophic growth factor (BDNF) and the free fatty acid receptor 1 known as GPR40.\u00a0 When they inhibited the action of these two proteins in the hypothalamus, the formation of new neurons diminished.<\/p>\n

 <\/p>\n

\"016-021_CAPA_Obesidade_240-01\"<\/a><\/p>\n

The blood-brain barrier\u00a0 <\/strong>
\nFats appear to exert positive and negative effects directly on certain regions of the brain because, in more instances than was previously believed, they are able to cross the blood-brain barrier.\u00a0 This is the name given to the protective system that prevents substances present in the blood and considered exogenous or potentially dangerous from entering the brain.\u00a0 The barrier is semi-permeable, allowing some substances to pass while blocking others, and it coats all blood vessels of the brain.\u00a0 It is composed of endothelial cells whose junctions (the space between two contiguous cells) are extremely tight and reinforced by astrocytes, brain cells that provide extra support and are10 times more abundant than neurons.\u00a0 As a general rule, scholars always believed that fats in the blood were unable to cross the barrier.<\/p>\n

This perception has changed over the past 10 years, however.\u00a0 In 2005, an article signed by Velloso and his colleagues at Unicamp and the University of S\u00e3o Paulo (USP), published in the journal Endocrinology, <\/em>was one of the first to suggest that obese mice presented chronic inflammation in the hypothalamus and developed resistance to insulin and leptin, conditions that open the door to the occurrence of diabetes.\u00a0 \u201cThe neurons of the animals that consumed a diet rich in saturated fats stopped responding to these hormones after a few weeks,\u201d Velloso says.\u00a0 Insulin is responsible for transporting glucose to the cell interiors where sugar is converted into life-sustaining energy.\u00a0 Leptin induces satiety.<\/p>\n

These alterations in the hypothalamus are enough to create an environment that favors maintenance of obesity and emergence of disorders generally associated with weight gain, such as diabetes and heart problems \u2013 and the root of this malfunction is the death of neurons caused by permanently adopting a diet rich in saturated fats.<\/p>\n

 <\/p>\n

\"016-021_CAPA_Obesidade_240-02\"<\/a><\/p>\n

Extent of the brain damage<\/strong>
\nIn more recent studies, the group led by Velloso and teams from other research centers abroad have focused on trying to characterize the extent of the brain damage caused by this pattern of eating.\u00a0 The researchers believe that continuous excessive consumption of fatty acids leads to a rupture of the blood-brain barrier in certain sub-regions of the hypothalamus.\u00a0 When this brain defense system is disrupted, chronic inflammation and potential death of POMC-type neurons occurs.\u00a0 \u201cA slight change in the barrier can produce effects in the hypothalamus, a very sensitive region of the brain,\u201d says neurologist Fernando Cendes, a professor at the FCM-Unicamp and coordinator of the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN), another RIDC.\u00a0 Studies using magnetic resonance to analyze the human hypothalamus are the result of intensive collaborative work between the OCRC and BRAINN.<\/p>\n

Apparently, the impact of a diet rich in saturated fats occurs in well-defined sectors at the base of the brain.\u00a0 A study conducted by pharmacologist Albina Ramalho as part of her doctoral dissertation to be defended in late February 2016 at FCM-Unicamp found evidence that damage to the blood-brain barrier induced by weight gain is prematurely manifested in a region adjacent to the hypothalamus known as the median eminence.\u00a0 \u201cThis is the first place where the barrier is able to be disrupted,\u201d says Ramalho, whose research is being carried out under Velloso and Professor Eliana de Ara\u00fajo.\u00a0 After having been subjected to four weeks of a diet consisting of 30% saturated fat, the tanycytes, elongated cells of the glia that connect the central nervous system to the blood vessels of the barrier, presented loss of cohesion and linearity.\u00a0 In three other areas near the median eminence, the deleterious effects of the hyperlipid diet took more time to appear.<\/p>\n

There is evidence that the tanycytes are the cells responsible for \u201cdeciding\u201d what passes through the barrier.\u00a0 To strengthen the hypothesis that the consumption of foods with high saturated fat content de-structures the brain\u2019s defense system in the area of the hypothalamus, Ramalho also injected the animals with a type of sugar that does not normally cross the barrier, combined with a substance that emits fluorescence.\u00a0 In the rodents subjected to a diet rich in fats, the polysaccharide penetrated the barrier and was found in the median eminence and in the hypothalamus.<\/p>\n

\"Saturated

Chris Goldberg\/FLICKR<\/span>Saturated fats found in red meats and trans fats commonly found in processed foods, are thought to alter the functioning of brain sensors of hunger and satietyChris Goldberg\/FLICKR<\/span><\/p><\/div>\n

Obesity as a disease<\/strong>
\nOne of the obvious problems encountered in studies on the impact on the brain of diets rich in fat, is attempting to reproduce, in humans, experiments conducted using animals.\u00a0 Ultimately, in order to determine impacts on the central nervous system, the mice are sacrificed at the end of the studies and their brains extracted.\u00a0 This constraint is partially circumvented by the use of non-invasive imaging techniques such as functional magnetic resonance, which allows observation of activation in certain areas of the brain in real time.\u00a0 A 2011 study by Velloso\u2019s group, also published in the journal Diabetes, <\/em>indicates that the hypothalamus of morbidly obese, formerly obese (those who underwent bariatric surgery) and lean individuals reacts differently to food stimuli.\u00a0 The lean subjects felt satiated more quickly than the obese subjects after receiving glucose.\u00a0 \u201cThose who had undergone surgery presented an intermediate pattern of hypothalamus activation,\u201d Velloso says.\u00a0 \u201cBut we don\u2019t know if this is maintained over time because many regain the weight.\u201d<\/p>\n

Physiologist Jos\u00e9 Donato Junior, a researcher at the USP Biomedical Sciences Institute (ICB), praises the results obtained by his colleagues at the OCRC.\u00a0 \u201cThey are reinforcing the notion that obesity is not simply the result of\u00a0 individual laziness,\u201d says Donato Junior, who is currently focusing on the study of risk factors that lead to weight gain in women.\u00a0 \u201cObesity has to be viewed as a disease.\u201d\u00a0 The USP researcher expresses some reservations, however.\u00a0 The studies with mice cannot simply be transposed to human circumstances.\u00a0 \u201cNo one consumes a diet consisting of 30% or 40% saturated fats like that fed to the mice in the study,\u201d Donato Junior says.\u00a0 \u201cBut this criticism applies to experiments all over the world, including my own.\u00a0 Metabolic processes are accelerated and exaggerated in animal models.\u201d<\/p>\n

The hypothalamic lesions induced by excessive consumption of saturated fats must be linked to many cases of obesity, but not to all of them, notes Donato Junior.\u00a0 The action of the neurotransmitter dopamine, of vital importance for the functioning of the reward system, could be behind some of the occurrences of individual obesity.\u00a0 \u201cAn individual may have no hypothalamic lesion at all and simply be addicted to eating,\u201d he says.<\/p>\n

For Brazilian biochemist Marcelo Dietrich, a researcher at Yale University School of Medicine, who is also studying the effects of a diet rich in saturated fats on the hunger and satiety circuits in the hypothalamus, determining whether brain inflammation is a cause or an effect of obesity is no simple task.\u00a0 \u201cThe hypothalamus is viewed as a high- functioning brain circuit, found in nearly all mammals,\u201d Dietrich says.\u00a0 \u201cBut between 7% and 10% of all cases of childhood obesity have a genetic origin and also activate this same circuit.\u201d<\/p>\n

No one doubts that several factors can increase or decrease an individual\u2019s risk of becoming obese, and these include type of diet, metabolic and genetic disorders and habits linked to lifestyle (engaging or not in regular exercise, for example).\u00a0 We also know that eating foods high in saturated or trans fats causes one to gain weight.\u00a0 And, as is commonly known today, excessive weight gain increases the risk of diabetes, heart problems and cancer.\u00a0 The major contribution of the studies by Velloso\u2019s group have been to reinforce the role that various types of fat \u2013 saturated and unsaturated\u00a0 \u2013 appear to play in the function of the system that regulates hunger, satiety and energy expenditure located in the hypothalamus.\u00a0 As with the heart, \u201cgood\u201d fats apparently mitigate the brain damage associated with the intake of \u201cbad\u201d fats.\u00a0 \u201cBrain inflammation may or may not cause obesity, but it alters this condition and helps perpetuate it,\u201d says neurologist Fernando Cendes.<\/p>\n

Project<\/strong>
\nObesity and Comorbidities Research Center (n\u00ba 2013\/07607-8<\/a>); Grant Mechanism<\/strong>\u00a0Research, Innovation and Dissemination Center (RIDC); Principal Investigator<\/strong>\u00a0L\u00edcio Velloso (FCM-Unicamp); Investment<\/strong>\u00a0R$\u00a0 14,579,597.41 (for the entire RIDC).<\/p>\n

Scientific articles<\/em>
\nNASCIMENTO, L. F. R. et al<\/em>. Omega-3 fatty acids induce neurogenesis of predominantly POMC-expressing cells in the hypothalamus<\/a>.\u00a0 Diabetes<\/strong>. October 28, 2015.
\nVAN DE SANDE-LEE, S. et al<\/em>. Partial reversibility of hypothalamic dysfunction and changes in brain activity after body mass reduction in obese subjects.<\/a> Diabetes<\/strong>. V. 60, No. 6, p. 1699-704. June 2011.
\nDE SOUSA, C. T. et al<\/em>. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus.<\/a> Endocrinology<\/strong>. V. 146. No. 10, p. 4192-9. October 2005.<\/p>\n","protected":false},"excerpt":{"rendered":"Unsaturated fatty acids could reverse damage to the brain of obese individuals","protected":false},"author":13,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"_exactmetrics_skip_tracking":false,"_exactmetrics_sitenote_active":false,"_exactmetrics_sitenote_note":"","_exactmetrics_sitenote_category":0,"footnotes":""},"categories":[156],"tags":[247,250,251],"coauthors":[101],"class_list":["post-219781","post","type-post","status-publish","format-standard","hentry","category-cover","tag-medicine","tag-neuroscience","tag-nutrition"],"acf":[],"_links":{"self":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/219781","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/users\/13"}],"replies":[{"embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/comments?post=219781"}],"version-history":[{"count":0,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/posts\/219781\/revisions"}],"wp:attachment":[{"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/media?parent=219781"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/categories?post=219781"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/tags?post=219781"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/revistapesquisa.fapesp.br\/en\/wp-json\/wp\/v2\/coauthors?post=219781"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}