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A fat that fights obesity

Unsaturated fatty acids like omega-3 promote the birth of neurons and could reverse damage to the brain of obese individuals

Salmon and flaxseed: foods rich in unsaturated fats such as omega-3 seem to fight brain inflammation associated with weight gain

LÉO RAMOSSalmon and flaxseed: foods rich in unsaturated fats such as omega-3 seem to fight brain inflammation associated with weight gainLÉO RAMOS

The human body’s reactions to the intake of diets rich in fats are complex and characterized by aspects that are both positive and negative.  The heart is probably the organ in which the potential risks and benefits of this dual relationship are best known.  Some types of fatty acids tend to deposit in the body’s tissues, raising blood pressure and increasing the risk of heart problems.  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.  Other forms, such as unsaturated fats, seem to help maintain lower cholesterol and blood pressure levels and help keep blood vessels relatively clear.  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 – the brain.

New studies have raised evidence that obesity, generally characterized by an excessive consumption of saturated and trans fats as part of an individual’s eating habits, coupled with an unhealthy lifestyle, could produce chronic inflammation of the hypothalamus.  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.  Thus, the improper functioning of the circuits that regulate eating behavior—the individual feels hungry after a hearty meal—contribute to perpetuating weight gain.  This is one of the harmful effects that can arise from the accumulation of saturated fats in the central nervous system.  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.

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.  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.  The other group received docosahexaenoic acid (DHA), a polyunsaturated fatty acid of the omega-3 family, through direct injection into the hypothalamus.  A third group received  only the addition of salt solution to their diet.

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.  The control group presented no formation of new neurons.  “This is the first study that shows neurogenesis in the hypothalamus induced by a food nutrient, like a diet rich in omega-3,” says physician Lício Velloso of the School of Medical Sciences of the University of Campinas (FCM-Unicamp), coordinator of the center and the animal study.  “Perhaps the unsaturated fats can be a way to minimize neuron death caused by brain inflammation linked to obesity.”  The study was published in the American journal Diabetes on October 28, 2015.

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.  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.  Thus, the compound is a useful molecular tool for ascertaining whether the birth of neurons in the brain has occurred.

In the experiment conducted at the OCRC, the researchers generated images of the hypothalamic region of obese mice obtained using confocal microscopy.  In the animals in which there was no neurogenesis, only red cells that represent the POMC neurons already present in the rodents appeared.  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.  “We 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,” 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).  The RIDC researchers also found evidence that the DHA stimulated neurogenesis by interacting with two proteins:  the brain-derived neurotrophic growth factor (BDNF) and the free fatty acid receptor 1 known as GPR40.  When they inhibited the action of these two proteins in the hypothalamus, the formation of new neurons diminished.

 

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The blood-brain barrier 
Fats 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.  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.  The barrier is semi-permeable, allowing some substances to pass while blocking others, and it coats all blood vessels of the brain.  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.  As a general rule, scholars always believed that fats in the blood were unable to cross the barrier.

This perception has changed over the past 10 years, however.  In 2005, an article signed by Velloso and his colleagues at Unicamp and the University of São Paulo (USP), published in the journal Endocrinology, 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.  “The neurons of the animals that consumed a diet rich in saturated fats stopped responding to these hormones after a few weeks,” Velloso says.  Insulin is responsible for transporting glucose to the cell interiors where sugar is converted into life-sustaining energy.  Leptin induces satiety.

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 – and the root of this malfunction is the death of neurons caused by permanently adopting a diet rich in saturated fats.

 

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Extent of the brain damage
In 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.  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.  When this brain defense system is disrupted, chronic inflammation and potential death of POMC-type neurons occurs.  “A slight change in the barrier can produce effects in the hypothalamus, a very sensitive region of the brain,” says neurologist Fernando Cendes, a professor at the FCM-Unicamp and coordinator of the Brazilian Research Institute for Neuroscience and Neurotechnology (BRAINN), another RIDC.  Studies using magnetic resonance to analyze the human hypothalamus are the result of intensive collaborative work between the OCRC and BRAINN.

Apparently, the impact of a diet rich in saturated fats occurs in well-defined sectors at the base of the brain.  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.  “This is the first place where the barrier is able to be disrupted,” says Ramalho, whose research is being carried out under Velloso and Professor Eliana de Araújo.  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.  In three other areas near the median eminence, the deleterious effects of the hyperlipid diet took more time to appear.

There is evidence that the tanycytes are the cells responsible for “deciding” what passes through the barrier.  To strengthen the hypothesis that the consumption of foods with high saturated fat content de-structures the brain’s 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.  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.

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 satiety

Chris Goldberg/FLICKRSaturated 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

Obesity as a disease
One 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.  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.  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.  A 2011 study by Velloso’s group, also published in the journal Diabetes, indicates that the hypothalamus of morbidly obese, formerly obese (those who underwent bariatric surgery) and lean individuals reacts differently to food stimuli.  The lean subjects felt satiated more quickly than the obese subjects after receiving glucose.  “Those who had undergone surgery presented an intermediate pattern of hypothalamus activation,” Velloso says.  “But we don’t know if this is maintained over time because many regain the weight.”

Physiologist José Donato Junior, a researcher at the USP Biomedical Sciences Institute (ICB), praises the results obtained by his colleagues at the OCRC.  “They are reinforcing the notion that obesity is not simply the result of  individual laziness,” says Donato Junior, who is currently focusing on the study of risk factors that lead to weight gain in women.  “Obesity has to be viewed as a disease.”  The USP researcher expresses some reservations, however.  The studies with mice cannot simply be transposed to human circumstances.  “No one consumes a diet consisting of 30% or 40% saturated fats like that fed to the mice in the study,” Donato Junior says.  “But this criticism applies to experiments all over the world, including my own.  Metabolic processes are accelerated and exaggerated in animal models.”

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.  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.  “An individual may have no hypothalamic lesion at all and simply be addicted to eating,” he says.

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.  “The hypothalamus is viewed as a high- functioning brain circuit, found in nearly all mammals,” Dietrich says.  “But between 7% and 10% of all cases of childhood obesity have a genetic origin and also activate this same circuit.”

No one doubts that several factors can increase or decrease an individual’s 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).  We also know that eating foods high in saturated or trans fats causes one to gain weight.  And, as is commonly known today, excessive weight gain increases the risk of diabetes, heart problems and cancer.  The major contribution of the studies by Velloso’s group have been to reinforce the role that various types of fat – saturated and unsaturated  – appear to play in the function of the system that regulates hunger, satiety and energy expenditure located in the hypothalamus.  As with the heart, “good” fats apparently mitigate the brain damage associated with the intake of “bad” fats.  “Brain inflammation may or may not cause obesity, but it alters this condition and helps perpetuate it,” says neurologist Fernando Cendes.

Project
Obesity and Comorbidities Research Center (nº 2013/07607-8); Grant Mechanism Research, Innovation and Dissemination Center (RIDC); Principal Investigator Lício Velloso (FCM-Unicamp); Investment R$  14,579,597.41 (for the entire RIDC).

Scientific articles
NASCIMENTO, L. F. R. et al. Omega-3 fatty acids induce neurogenesis of predominantly POMC-expressing cells in the hypothalamusDiabetes. October 28, 2015.
VAN DE SANDE-LEE, S. et al. Partial reversibility of hypothalamic dysfunction and changes in brain activity after body mass reduction in obese subjects. Diabetes. V. 60, No. 6, p. 1699-704. June 2011.
DE SOUSA, C. T. et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. V. 146. No. 10, p. 4192-9. October 2005.

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