Posts tagged obesity
Articles and news from the latest research reports.
Changes in brain chemistry sustain obesity
With obesity reaching epidemic levels in some parts of the world, scientists have only begun to understand why it is such a persistent condition. A study in the Journal of Biological Chemistry adds substantially to the story by reporting the discovery of a molecular chain of events in the brains of obese rats that undermined their ability to suppress appetite and to increase calorie burning.
It’s a vicious cycle, involving a breakdown in how brain cells process key proteins, that allows obesity to beget further obesity. But in a finding that might prove encouraging in the long term, the researchers at Brown University and Lifespan also found that they could intervene to break that cycle by fixing the core protein-processing problem.
Before the study, scientists knew that one mechanism in which obesity perpetuates itself was by causing resistance to leptin, a hormone that signals the brain about the status of fat in the body. But years ago senior author Eduardo A. Nillni, professor of medicine at Brown University and a researcher at Rhode Island Hospital, observed that after meals obese rats had a dearth of another key hormone — alpha-MSH — compared to rats of normal weight.
Alpha-MSH has two jobs in parts of the hypothalamus region of the brain. One is to suppress the activity of food-seeking brain cells. The second is to signal other brain cells to produce the hormone TRH, which prompts the thyroid gland to spur calorie burning activity in the body.
In the obese rats alpha-MSH was low, despite an abundance of leptin and despite normal levels of gene expression both for its biochemical precursor protein called pro-opiomelanocortin (POMC) and for a key enzyme called PC2 that processes POMC in brain cells. There had to be more to the story than just leptin, and it wasn’t a problem with expressing the needed genes.
Nillni and his co-authors, including lead authors Isin Cakir and Nicole Cyr, conducted the new study to find out where the alpha-MSH deficit was coming from. Nillni said he suspected that the problem might lie in the brain cells’ mechanism for processing the POMC protein to make alpha-MSH.
Protein processing problems
To do their work, the team fed some rats a high-calorie diet and fed others a normal diet for 12 weeks. The overfed rats developed the condition of “diet-induced obesity.” The team then studied the hormone levels and brain cell physiology of the rats. They also tested their findings by experimenting with the biochemistry of key individual cells on the lab bench.
They found that in the obese rats, a key “machine” in the brain cells’ assembly line of protein-making, called the endoplasmic reticulum (ER), becomes stressed and overwhelmed. The overloaded ER apparently fumbles the proper handling of PC2, perhaps discarding it because it can’t be folded up properly. The PC2 levels they measured in obese rats, for example, were 53 percent lower than in normal rats. Alpha-MSH peptides were also barely more than half as abundant in obese rats as they were in healthy rats.
“In our study we showed that what actually prevents the production of more alpha-MSH peptide is that ER stress was decreasing the biosynthesis of POMC by affecting one key enzyme that is essential for the formation of alpha-MSH,” Nillni said. “This is so novel. Nobody ever looked at that.”
Novel as it was, the story — a stressed ER mishandles PC2, which leaves POMC unfolded, which impedes alpha-MSH production — needed experimental confirmation.
The team provided that confirmation in several ways: In obese rats they measured elevated levels of known markers of ER stress. They also purposely induced ER stress in cells using pharmacological agents and saw that both PC2 and Alpha-MSH levels dropped.
Next they conducted an experiment to see if fixing ER stress would improve alpha-MSH production. They treated lean and obese rats for two days with a chemical called TUDCA, which is known to alleviate ER stress. If ER stress is responsible for alpha-MSH production problems, the researchers would see alpha-MSH recover in obese rats treated with TUDCA. Sure enough, while TUDCA didn’t increase alpha-MSH production in normal rats, it increased it markedly in the obese rats.
Similarly on the benchtop they took mouse neurons that produce PC2 and POMC and pretreated some with a similar chemical called PBA that prevents ER stress. They left others untreated. Then they induced ER stress in all the cells. Under that ER stress, those that had been pretreated with PBA produced about twice as much PC2 as those that had not.
Nillni cautioned that although his team found ways to restore PC2 and alpha-MSH by treating ER stress in living rats and individual cells, the agents used in the study are not readily applicable as medicines for treating obesity in humans. There could well be unknown and unwanted side effects, for example, and TUDCA is not approved for human use by the U.S. Food and Drug Administration.
But by laying out the exact mechanism responsible for why the brains of the obese rats failed to curb appetite or spur greater calorie burning, Nillni said, the study points drug makers to several opportunities where they can intervene to break this new, vicious cycle that helps obesity to perpetuate itself.
“Understanding the central control of energy-regulating neuropeptides during diet-induced obesity is important for the identification of therapeutic targets to prevent and or mitigate obesity pathology,” the authors wrote.
Study identifies key shift in the brain that creates drive to overeat
A team of American and Italian neuroscientists has identified a cellular change in the brain that accompanies obesity. The findings could explain the body’s tendency to maintain undesirable weight levels, rather than an ideal weight, and identify possible targets for pharmacological efforts to address obesity.
The findings, published in the Proceedings of the National Academy of Sciences Early Edition this week, identify a switch that occurs in neurons within the hypothalamus. The switch involves receptors that trigger or inhibit the release of the orexin A peptide, which stimulates the appetite, among other behaviors. In normal-weight mice, activation of this receptor decreases orexin A release. In obese mice, activation of this receptor stimulates orexin A release.
“The striking finding is that you have a massive shift of receptors from one set of nerve endings impinging on these neurons to another set,” said Ken Mackie, professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences at IU Bloomington. “Before, activating this receptor inhibited the secretion of orexin; now it promotes it. This identifies potential targets where an intervention could influence obesity.”
The work is part of a longstanding collaboration between Mackie’s team at the Gill Center for Biomolecular Science at IU Bloomington and Vincenzo Di Marzo’s team at the Institute of Biomolecular Chemistry in Pozzuoli, Italy. Both teams study the endocannabinoid system, which is composed of receptors and signaling chemicals that occur naturally in the brain and have similarities to the active ingredients in cannabis, or marijuana. This neurochemical system is involved in a variety of physiological processes, including appetite, pain, mood, stress responses and memory.
Food consumption is controlled in part by the hypothalamus, a portion of the brain that regulates many essential behaviors. Like other important body systems, food consumption is regulated by multiple neurochemical systems, including the endocannabinoid system, representing what Mackie describes as a “balance of a very fine web of regulatory networks.”
An emerging idea, Mackie said, is that this network is reset during obesity so that food consumption matches maintenance of current weight, not a person’s ideal weight. Thus, an obese individual who loses weight finds it difficult to keep the weight off, as the brain signals the body to eat more in an attempt to return to the heavier weight.
Using mice, this study found that in obesity, CB1 cannabinoid receptors become enriched on the nerve terminals that normally inhibit orexin neuron activity, and the orexin neurons produce more of the endocannabinoids to activate these receptors. Activating these CB1 receptors decreases inhibition of the orexin neurons, increasing orexin A release and food consumption.
“This study identifies a mechanism for the body’s ongoing tendency to return to the heavier weight,” Mackie said.
The researchers conducted several experiments with mice to understand how this change takes place. They uncovered a role of leptin, a key hormone made by fat cells that influences metabolism, hunger and food consumption. Obesity causes leptin levels to be chronically high, making brain cells less sensitive to its actions, which contributes to the molecular switch that leads to the overproduction of orexin.
(Source: eurekalert.org)
Transgenic mice ready to fight obesity – and more
Scientists at the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw investigate mice with a very precisely modified genome. Because it is possible to turn off the Dicer gene in adult mice, they can be used to investigate the processes related to such cognitive functions such as learning and memory. Also Nencki scientists have just shown that the new transgenic mouse is suitable to study metabolic dysfunctions resulting in obesity.
Studies on the Dicer gene and its impact on the cognitive and metabolic processes are currently carried out at the Nencki Institute’s Laboratory of Animal Models, a core facility in the newly established Neurobiology Center. The Center has been built on Campus Ochota in Warsaw as part of a large European project called the Centre for Preclinical Research and Technology (CePT). This project, financed from the Operational Programme Innovative Economy, brings together 10 research institutions from Warsaw.
“No one needs convincing that knowledge about the function of individual human genes is absolutely fundamental in biology as well as medicine”, says Dr Witold Konopka, head of the Laboratory of Animal Models. “But how do we determine a gene’s function, if no genetic modifications in humans are allowed? The only method is to create an animal, for example a mouse with genes turned on or off to model the studied illness. This is easy to say, but difficult to do, especially when the involved genes are really important for each cell”.
For several years Dr Konopka has been involved in research on the Dicer gene in mice. This gene, the analogue of which can be found also in the human genome, is responsible for creating a protein which reduces RNA molecules to short, 20-nucleotide fragments, important in regulating the activity of other genes. The Dicer gene needs to be active for proper functioning of the cell. It cannot be simply turned off in zygote, because the resulting defect would make the proper development of the zygote impossible.
Preparation of a transgenic mouse, in which the Dicer gene could be blocked in adulthood, takes a year and a half. This process starts with surrounding the Dicer gene on the DNA chain with two sequences known as loxP. This is done on stem cells, which are then injected into the embryo. Since the Dicer gene remains active, the embryo develops normally. At the same time the animal zygote of the opposite sex is injected with a gene coding a protein known as recombinase Cre-ERT2. Molecules of this protein consist of a part containing the Cre enzyme and a fragment reacting to a chemical compound called tamoxifen, which prior to such reaction prohibits recombinase Cre-ERT2 from penetrating into the cell nucleus.
Adult mice of both types are then cross bred for progeny, which will inherit the Dicer gene surrounded with the loxP sequences as well as the gene coding for recombinase from its parents. A mouse of this type has been created thanks to a joint effort of research groups from different world research centres such as the German Cancer Research Center (DKFZ) in Germany or the Imperial College London in the United Kingdom.
In order to turn off the Dicer gene in such adult mouse, it is enough to administer tamoxifen to them for a few days, which accumulates in neurons and allows the recombinase to penetrate into the cell nucleus. The Cre enzyme recognises the loxP sequence and removes the coding fragment with the Dicer gene.
“The first mice, in which the Dicer gene could be switched off at any time, were received by me a few years ago during my postdoctoral fellowship in the German Cancer Research Center in Heidelberg. Currently we breed such mice also the Nencki’s Laboratory of Animal Models. But breeding such animals constitutes only a part of the task. If we want to use them for research, they have to be appropriately characterized”, explains Dr Konopka.
Traits of mice used for scientific research have to be well known. Without such knowledge researchers cannot determine whether a change observed in the appearance or behaviour of the animal is related to turning off the gene. “Two years ago we have characterized the cognitive processes of these new mice. We have determined that after turning off the Dicer gene the animals showed better memory than the controls”, says Dr Konopka. But about five months after deleting the Dicer gene from the brain, the mice scored below the level of the control group on their cognitive abilities, which could be related to dying neurons devoid of the Dicer gene. Currently scientists have just finished analysing changes occurring in metabolic processes of those new mice, which for 3-4 weeks after turning off the Dicer gene eat more and gain weight faster, whereupon their appetite goes back to normal, but higher weight of their bodies’ remains.
“Before we have established with the required accuracy, how our mice learn and remember. Now we are certain, that the same mice can be used to investigate obesity and we plan to do that soon. But in our new lab we will not only conduct studies on disease models. We would also like to generate new transgenic animals for other research centres”, emphasizes Dr Konopka.
(Source: alphagalileo.org)
Binge Eating Curbed by Deep Brain Stimulation in Animal Model
Deep brain stimulation (DBS) in a precise region of the brain appears to reduce caloric intake and prompt weight loss in obese animal models, according to a new study led by researchers at the University of Pennsylvania. The study, reported in the Journal of Neuroscience, reinforces the involvement of dopamine deficits in increasing obesity-related behaviors such as binge eating, and demonstrates that DBS can reverse this response via activation of the dopamine type-2 receptor.
“Based on this research, DBS may provide therapeutic relief to binge eating, a behavior commonly seen in obese humans, and frequently unresponsive to other approaches,” said senior author Tracy L. Bale, PhD, associate professor of neuroscience in Penn’s School of Veterinary Medicine’s Department of Animal Biology and in the Perelman School of Medicine’s Department of Psychiatry. DBS is currently used to reduce tremors in Parkinson’s disease and is under investigation as a therapy for major depression and obsessive-compulsive disorder.
Nearly 50 percent of obese people binge eat, uncontrollably consuming palatable highly caloric food within a short period of time. In this study, researchers targeted the nucleus accumbens, a small structure in the brain reward center known to be involved in addictive behaviors. Mice receiving the stimulation ate significantly less of the high fat food compared to mice not receiving DBS. Following stimulation, mice did not compensate for the loss of calories by eating more. However, on days when the device was turned off, binge eating resumed.
Researchers also tested the long-term effects of DBS on obese mice that had been given unlimited access to high-fat food. During four days of continuous stimulation, the obese mice consumed fewer calories and, importantly, their body weight dropped. These mice also showed improvement in their glucose sensitivity, suggestive of a reversal of type 2 diabetes.
“These results are our best evidence yet that targeting the nucleus accumbens with DBS may be able to modify specific feeding behaviors linked to body weight changes and obesity,” Bale added.
“Once replicated in human clinical trials, DBS could rapidly become a treatment for people with obesity due to the extensive groundwork already established in other disease areas,” said lead author Casey Halpern, MD, resident in the Department of Neurosurgery of the Perelman School of Medicine at the University of Pennsylvania.
(Source: uphs.upenn.edu)
Ever since the appetite-regulation hormone called leptin was discovered in 1994, scientists have sought to understand the mechanisms that control its action. It was known that leptin was made by fat cells, reduced appetite and interacted with insulin , but the precise molecular details of its function —details that might enable the creation of a new treatment for obesity — remained elusive.
Now, University of Texas Medical Branch at Galveston researchers have revealed a significant part of one of those mechanisms, identifying a protein that can interfere with the brain’s response to leptin. They’ve also created a compound that blocks the protein’s action — a potential forerunner to an anti-obesity drug.
In experiments with mice fed a high-fat diet, scientists from UTMB and the University of California, San Diego explored the role of the protein, known as Epac1, in blocking leptin’s activity in the brain. They found that mice genetically engineered to be unable to produce Epac1 had lower body weights, lower body fat percentages, lower blood-plasma leptin levels and better glucose tolerance than normal mice.
When the researchers used a specially developed “Epac inhibitor” to treat brain-slice cultures taken from normal laboratory mice, they found elevated levels of proteins associated with greater leptin sensitivity. Similar results were seen in the genetically engineered mice that lacked the Epac1 gene. In addition, normal mice treated with the inhibitor had significantly lower levels of leptin in their blood plasma — an indication that Epac1 also affected their leptin levels.
“We found that we can increase leptin sensitivity by creating mice that lack the genes for Epac1 or through a pharmacological intervention with our Epac inhibitor,” said UTMB professor Xiaodong Cheng, lead author of a paper on the study that recently appeared on the cover of Molecular and Cellular Biology. “The knockout mice gave us a way to tease out the function of the protein, and the inhibitor served as a pharmacological probe that allowed us to manipulate these molecules in the cells.”
Cheng and his colleagues suspected a connection between Epac1 and leptin because Epac1 is activated by cyclic AMP, a signaling molecule linked to metabolism and leptin production and secretion. Cyclic AMP is tied to a multitude of other cell signaling processes, many of which are targeted by current drugs. Cheng believes that understanding how it acts through Epac1 (and another form of the protein called Epac2) will also generate new pharmaceutical possibilities — possibly including a drug therapy that will help fight obesity and diabetes.
“We refer to these Epac inhibitors as pharmacological probes, and while they are still far away from drugs, pharmaceutical intervention is always our eventual goal,” Cheng said. “We were the first to develop Epac inhibitors, and now we’re working very actively with Dr. Jia Zhou, a UTMB medicinal chemist, to modify them and improve their properties. In addition, we are collaborating with colleagues at the NIH National Center for Advancing Translational Sciences in searching for more potent and selective pharmacological probes for Epac proteins.”
Molecular hub links obesity, heart disease to high blood pressure
Obesity, heart disease, and high blood pressure (hypertension) are all related, but understanding the molecular pathways that underlie cause and effect is complicated.
A new University of Iowa study identifies a protein within certain brain cells as a communications hub for controlling blood pressure, and suggests that abnormal activation of this protein may be a mechanism that links cardiovascular disease and obesity to elevated blood pressure.
“Cardiovascular diseases are the leading cause of death worldwide, and hypertension is a major cardiovascular risk factor,” says Kamal Rahmouni, UI associate professor of pharmacology and internal medicine, and senior study author. “Our study identifies the protein called mTORC1 in the hypothalamus as a key player in the control of blood pressure. Targeting mTORC1 pathways may, therefore, be a promising strategy for the management of cardiovascular risk factors.”
The hypothalamus is a small region of the brain that is responsible for maintaining normal function for numerous bodily processes, including blood pressure, body temperature, and glucose levels. Signaling of mTORC1 protein in the hypothalamus has previously been shown to affect food intake and body weight.
The new study, which was published April 2 in the journal Cell Metabolism, shows that the mTORC1 protein is activated by small molecules and hormones that are associated with obesity and cardiovascular disease, and this activation leads to dramatic increases in blood pressure.
Leucine is an amino acid that we get from food, which is known to activate mTORC1. The UI researchers showed that activating mTORC1 in rat brains with leucine increased activity in the nerves that connect the brain to the kidney, an important organ in blood pressure control. The increased nerve activity was accompanied by a rise in blood pressure. Conversely, blocking this mTORC1 activation significantly blunted leucine’s blood pressure-raising effect.
This finding may have direct clinical relevance as elevated levels of leucine have been correlated with an increased risk of high blood pressure in patients with cardiovascular disease.
“Our new study suggests a mechanism by which leucine in the bloodstream might increase blood pressure,” Rahmouni says.
Previous work has also suggested that mTORC1 is a signaling hub for leptin, a hormone produced by fat cells, which has been implicated in obesity-related hypertension.
Rahmouni and his colleagues showed that leptin activates mTORC1 in a specific part of the hypothalamus causing increased nerve activity and a rise in blood pressure. These effects are blocked by inhibiting activation of mTORC1.
“Our study shows that when this protein is either activated or inhibited in a very specific manner, it can cause dramatic changes in blood pressure,” Rahmouni says. “Given the importance of this protein for the control of blood pressure, any abnormality in its activity might explain the hypertension associated with certain conditions like obesity and cardiovascular disease.”
Rahmouni and his team hope that uncovering the details of the pathways linking mTORC1 activation and high blood pressure might lead to better treatments for high blood pressure in patients with cardiovascular disease and obesity.
(Source: now.uiowa.edu)
Couch Potatoes May Be Genetically Predisposed to Being Lazy
Studies show 97 percent of American adults get less than 30 minutes of exercise a day, which is the minimum recommended amount based on federal guidelines. New research from the University of Missouri suggests certain genetic traits may predispose people to being more or less motivated to exercise and remain active. Frank Booth, a professor in the MU College of Veterinary Medicine, along with his post-doctoral fellow Michael Roberts, were able to selectively breed rats that exhibited traits of either extreme activity or extreme laziness. They say these rats indicate that genetics could play a role in exercise motivation, even in humans.
“We have shown that it is possible to be genetically predisposed to being lazy,” Booth said. “This could be an important step in identifying additional causes for obesity in humans, especially considering dramatic increases in childhood obesity in the United States. It would be very useful to know if a person is genetically predisposed to having a lack of motivation to exercise, because that could potentially make them more likely to grow obese.”
In their study published in the American Journal of Physiology: Regulatory, Integrative and Comparative Physiology on April 3, 2013, Roberts and Booth put rats in cages with running wheels and measured how much each rat willingly ran on their wheels during a six-day period. They then bred the top 26 runners with each other and bred the 26 rats that ran the least with each other. They repeated this process through 10 generations and found that the line of running rats chose to run 10 times more than the line of “lazy” rats.
Once the researchers created their “super runner” and “couch potato” rats, they studied the levels of mitochondria in muscle cells, compared body composition and conducted thorough genetic evaluations through RNA deep sequencing of each rat.
“While we found minor differences in the body composition and levels of mitochondria in muscle cells of the rats, the most important thing we identified were the genetic differences between the two lines of rats,” Roberts said. “Out of more than 17,000 different genes in one part of the brain, we identified 36 genes that may play a role in predisposition to physical activity motivation.”
Now that the researchers have identified these specific genes, they plan on continuing their research to explore the effects each gene has on motivation to exercise.
Breakthrough in neuroscience could help re-wire appetite control
Researchers at the University of East Anglia (UEA) have made a discovery in neuroscience that could offer a long-lasting solution to eating disorders such as obesity.
It was previously thought that the nerve cells in the brain associated with appetite regulation were generated entirely during an embryo’s development in the womb and therefore their numbers were fixed for life.
But research published today in the Journal of Neuroscience has identified a population of stem cells capable of generating new appetite-regulating neurons in the brains of young and adult rodents.
Obesity has reached epidemic proportions globally. More than 1.4 billion adults worldwide are overweight and more than half a billion are obese. Associated health problems include type 2 diabetes, heart disease, arthritis and cancer. And at least 2.8 million people die each year as a result of being overweight or obese.
The economic burden on the NHS in the UK is estimated to be more than £5 billion annually. In the US, the healthcare cost tops $60 billion.
Scientists at UEA investigated the hypothalamus section of the brain – which regulates sleep and wake cycles, energy expenditure, appetite, thirst, hormone release and many other critical biological functions. The study looked specifically at the nerve cells that regulate appetite.
The researchers used ‘genetic fate mapping’ techniques to make their discovery – a method that tracks the development of stem cells and cells derived from them, at desired time points during the life of an animal.
They established that a population of brain cells called ‘tanycytes’ behave like stem cells and add new neurons to the appetite-regulating circuitry of the mouse brain after birth and into adulthood.
Lead researcher Dr Mohammad K. Hajihosseini, from UEA’s school of Biological Sciences, said: “Unlike dieting, translation of this discovery could eventually offer a permanent solution for tackling obesity.
“Loss or malfunctioning of neurons in the hypothalamus is the prime cause of eating disorders such as obesity.
“Until recently we thought that all of these nerve cells were generated during the embryonic period and so the circuitry that controls appetite was fixed.
“But this study has shown that the neural circuitry that controls appetite is not fixed in number and could possibly be manipulated numerically to tackle eating disorders.
“The next step is to define the group of genes and cellular processes that regulate the behaviour and activity of tanycytes. This information will further our understanding of brain stem cells and could be exploited to develop drugs that can modulate the number or functioning of appetite-regulating neurons.
“Our long-term goal of course is to translate this work to humans, which could take up to five or 10 years. It could lead to a permanent intervention in infancy for those predisposed to obesity, or later in life as the disease becomes apparent.”
Our internal clocks can become ticking time bombs for diabetes and obesity
New research in The FASEB Journal using mice suggests that disrupting our internal clocks can lead to a complete absence of 24-hour bodily rhythms and an immediate gain in body weight
If you’re pulling and all-nighter to finish a term paper, a new parent up all night with a fussy baby, or simply can’t sleep like you once could, then you may be snoozing on good health. That’s because new research published in The FASEB Journal used mice to show that proper sleep patterns are critical for healthy metabolic function, and even mild impairment in our circadian rhythms can lead to serious health consequences, including diabetes and obesity.
“We should acknowledge the unforeseen importance of our 24-hour rhythms for health,” said Claudia Coomans, Ph.D., a researcher involved in the work from the Department of Molecular Cell Biology in the Laboratory of Neurophysiology at Leiden University Medical Center in Leiden, Netherlands. “To quote Seneca ‘We should live according to nature (secundum naturam vivere).’”
To make this discovery, Coomans and colleagues exposed mice to constant light, which disturbed their normal internal clock function, and observed a gradual degradation of their bodies’ internal clocks until it reached a level that normally occurs when aging. Eventually the mice lost their 24-hour rhythm in energy metabolism and insulin sensitivity, indicating that relatively mild impairment of clock function had severe metabolic consequences.
“The good news is that some of us can ‘sleep it off’ to avoid obesity and diabetes,” said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “The bad news is that we can all get the metabolic doldrums when our normal day/night cycle is disrupted.”
Suzanne Dickson: Brain mechanisms of food reward
Studying what makes us want to eat, could help devise approaches to prevent obesity, which is becoming widespread in Europe.
Suzanne Dickson is a Professor of physiology and neuroendocrinology at the Institute of Neuroscience and Physiology, based at the Sahlgrenska Academy at the University of Gothenburg, Sweden. She tells youris.com about her involvement in the EU funded NeuroFAST project. Her focus is on the impact of appetite-regulating gut hormones on parts of the brain that influence food preference and food reward.
This research is also driven by the huge unmet need of treating the growing group of obese patients.
What is the focus of your work relating to food and the brain?
We work on food reward, which involves neurobiological circuits linked to the addiction process. We decided to work on this because increasing evidence linked excessive over-eating to brain pathways involved in reward, including pathways known to be targets for addictive drugs. Over-eating can be influenced by genetic predisposition traits, psychiatric diseases, cues from the environment that trigger expectation of a food reward. Other factors include socio-economic pressures, stressful lifestyle including stress in the workplace or home.
What is the nature of food reward?
Our specific focus is on the property of the reward value. If animals find food rewarding, they will display altered behaviours that indicate that the reward value of the food is changed. Members of our team are working with sugars, fats and combinations of the above. We have also been working in clinical projects with foods of similar taste but with altered caloric value. By targeting brain mechanisms involved in food reward, we hope to reveal new mechanisms that will help develop new treatment strategies for obesity.
We have studied an area of the brain called ventral tegmental area (VTA) is a key node in the brain’s reward pathway. It is the home of the dopamine cells that are activated by rewards, including food rewards. Its role is very complex. Many believe that these cells are involved in food searching behaviours or food motivation, for example. However, they also can be activated simply by cues associated with foods akin to deciding to consume a chocolate bar by the sight of one at the cashier in a supermarket and novelty of the reward stimulus appears to play a role.
Did you identify the difference between the brain’s pleasure center and hunger center?
The pleasure centres are involved in food intake that is linked to its reward value. Whether we are hungry or fed, by raising the reward value of food the reward system encourages us to eat more, especially rewarding food. This system has been critical during the evolution process to ensure survival from famine. In our modern environment that generates obesity, food reward is no longer our friend as it encourages us to over-indulge in sweet and fatty food, even when we are not hungry.
By contrast, the hunger pathways can be considered more primitive. They detect and respond to nutrient deficit. If we enter negative energy balance, homeostatic pathways become activated informing higher feeding networks to initiate feeding behaviours.
What strategies have studied to try and find ways to limit over-eating?
We have recently learned from the field of bariatric—weight loss—surgery that it is possible to change reward behaviour towards food. This involves unknown mechanisms that are likely linked to the brain’s food reward system. We focus particularly on a hormone called ghrelin whose secretion is altered after bariatric surgery. We hope to reveal new information that is of clinical and therapeutic relevance for future drug strategies for this disease area.
So far, in the laboratory, we have learned a lot about the basic brain mechanisms controlling food reward and the role played by gut hormones in regulating these. We therefore know a lot more about mechanisms—namely about the brain systems and circuits underpinning over-eating—especially for calorie dense foods.
(Image credit: Zorrilla Laboratory, The Scripps Research Institute)
