Posts tagged obesity
Posts tagged obesity
Obesity may alter the way we taste at the most fundamental level: by changing how our tongues react to different foods.
In a Nov. 13 study in the journal PLOS ONE, University at Buffalo biologists report that being severely overweight impaired the ability of mice to detect sweets.
Compared with slimmer counterparts, the plump mice had fewer taste cells that responded to sweet stimuli. What’s more, the cells that did respond to sweetness reacted relatively weakly.
The findings peel back a new layer of the mystery of how obesity alters our relationship to food.
“Studies have shown that obesity can lead to alterations in the brain, as well as the nerves that control the peripheral taste system, but no one had ever looked at the cells on the tongue that make contact with food,” said lead scientist Kathryn Medler, PhD, UB associate professor of biological sciences.
“What we see is that even at this level — at the first step in the taste pathway — the taste receptor cells themselves are affected by obesity,” Medler said. “The obese mice have fewer taste cells that respond to sweet stimuli, and they don’t respond as well.”
The research matters because taste plays an important role in regulating appetite: what we eat, and how much we consume.
How an inability to detect sweetness might encourage weight gain is unclear, but past research has shown that obese people yearn for sweet and savory foods though they may not taste these flavors as well as thinner people.
Medler said it’s possible that trouble detecting sweetness may lead obese mice to eat more than their leaner counterparts to get the same payoff.
Learning more about the connection between taste, appetite and obesity is important, she said, because it could lead to new methods for encouraging healthy eating.
“If we understand how these taste cells are affected and how we can get these cells back to normal, it could lead to new treatments,” Medler said. “These cells are out on your tongue and are more accessible than cells in other parts of your body, like your brain.”
The new PLOS ONE study compared 25 normal mice to 25 of their littermates who were fed a high-fat diet and became obese.
To measure the animals’ response to different tastes, the research team looked at a process called calcium signaling. When cells “recognize” a certain taste, there is a temporary increase in the calcium levels inside the cells, and the scientists measured this change.
The results: Taste cells from the obese mice responded more weakly not only to sweetness but, surprisingly, to bitterness as well. Taste cells from both groups of animals reacted similarly to umami, a flavor associated with savory and meaty foods.
Scientists discover key function in molecule that regulates sleep, metabolism and hunger
Why does hunger keep us awake and a full belly make us tired? Why do people with sleep disorders such as insomnia often binge eat late at night? What can sleep patterns tell us about obesity?
Sleep, hunger and metabolism are closely related, but scientists are still struggling to understand how they interact. Now, Brandeis University researchers have discovered a function in a molecule in fruit flies that may provide insight into the complicated relationship between sleep and food.
In the October issue of the journal Neuron, Brandeis scientists report that sNPF, a neuropeptide long known to regulate food intake and metabolism, is also an important component in regulating and promoting sleep. When researchers activated sNPF in fruit flies, the insects fell asleep almost immediately, awaking only long enough to eat before nodding off again. The flies were so sleepy that once they found a food source, they slept right on top of it for days — like falling asleep on a giant hamburger bun and waking up long enough to take a few nibbles before falling back to sleep.
When researchers returned sNPF functions to normal, the flies resumed their normal level of activity, leaving behind their couch potato ways.
The researchers, led by professor of biology Leslie Griffith, concluded that sNPF has an important regulatory function in sleep in addition to its previously known function coordinating behaviors such as eating and metabolism.
"This paper provides a nice bridge between feeding behavior and sleep behavior with just a single molecule," says Nathan Donelson, a post doctoral fellow in Griffith’s lab and one of the study’s lead authors.
Neurons use neuropeptides to communicate a range of brain functions including learning, metabolism, memory and social behaviors. In humans, Neuropeptide Y functions similarly to sNPF and has been studied as a possible drug target for obesity treatment.
But scientists don’t fully understand how regulating neuropeptide function at specific times and in specific cells affects sleeping and eating. By studying sNPF in fruit flies, scientists can learn which cells, neurotransmitters and genes are involved in eating and sleeping; what processes turn on and inhibit the behaviors, and how sleep cells are relevant to hunger drive.
"Our paper makes a significant step into tying all these things together," says Donelson, "and that is extremely important down the road to our understanding of human health."
The finding shows that certain parts of brain cells could play a critical role in anorexia, bulimia, binge eating disorder, and obesity.
Sixty years ago scientists could electrically stimulate a region of a mouse’s brain causing the mouse to eat, whether hungry or not. Now researchers from UNC School of Medicine have pinpointed the precise cellular connections responsible for triggering that behavior. The finding, published September 27 in the journal Science, lends insight into a cause for obesity and could lead to treatments for anorexia, bulimia nervosa, and binge eating disorder, the most prevalent eating disorder in the United States.
“The study underscores that obesity and other eating disorders have a neurological basis,” said senior study author Garret Stuber, PhD, assistant professor in the department of psychiatry and department of cell biology and physiology. He’s also a member of the UNC Neuroscience Center. “With further study, we could figure out how to regulate the activity of cells in a specific region of the brain and develop treatments.”
Cynthia Bulik, PhD, Distinguished Professor of Eating Disorders at UNC School of Medicine and the Gillings School of Global Public Health, said, “Stuber’s work drills down to the precise biological mechanisms that drive binge eating and will lead us away from stigmatizing explanations that invoke blame and a lack of willpower.” Bulik was not part of the research team.
Back in the 1950s, when scientists electrically stimulated a region of the brain called the lateral hypothalamus, they knew that they were stimulating many different types of brain cells. Stuber wanted to focus on one cell type — gaba neurons in the bed nucleus of the stria terminalis, or BNST. The BNST is an outcropping of the amygdala, the part of the brain associated with emotion. The BNST also forms a bridge between the amygdala and the lateral hypothalamus, the brain region that drives primal functions such as eating, sexual behavior, and aggression.
The BNST gaba neurons have a cell body and a long strand with branched synapses that transmit electrical signals into the lateral hypothalamus. Stuber and his team wanted to stimulate those synapses by using an optogenetic technique, an involved process that would let him stimulate BNST cells simply by shining light on their synapses.
Typically, brain cells don’t respond to light. So Stuber’s team used genetically engineered proteins — from algae — that are sensitive to light and used genetically engineered viruses to deliver them into the brains of mice. Those proteins then get expressed only in the BNST cells, including in the synapses that connect to the hypothalamus.
His team then implanted fiber optic cables in the brains of these specially-bred mice, and this allowed the researchers to shine light through the cables and onto BNST synapses. As soon as the light hit BNST synapses the mice began to eat voraciously even though they had already been well fed. Moreover, the mice showed a strong preference for high-fat foods.
“They would essentially eat up to half their daily caloric intake in about 20 minutes,” Stuber said. “This suggests that this BNST pathway could play a role in food consumption and pathological conditions such as binge eating.”
Stimulating the BNST also led the mice to exhibit behaviors associated with reward, suggesting that shining light on BNST cells enhanced the pleasure of eating. On the flip side, shutting down the BNST pathway caused mice to show little interest in eating, even if they had been deprived of food.
“We were able to really home in on the precise neural circuit connection that was causing this phenomenon that’s been observed for more than 50 years,” Stuber said.
The study, which uses technologies highlighted in the new National Institutes of Health Brain Initiative, suggests that faulty wiring in BNST cells could interfere with hunger or satiety cues and contribute to human eating disorders, leading people to eat even when they are full or to avoid food when they are hungry. Further research is needed to determine whether it would be possible to develop drugs that correct a malfunctioning BNST circuit.
“We want to actually observe the normal function of these cell types and how they fire electrical signals when the animals are feeding or hungry,” Stuber said. “We want to understand their genetic characteristics – what genes are expressed. For example, if we find cells that become really activated after binge eating, can we look at the gene expression profile to find out what makes those cells unique from other neurons.”
And that, Stuber said, could lead to potential targets for drugs to treat certain populations of patients with eating disorders.
Continuously eating fatty foods perturbs communication between the gut and brain, which in turn perpetuates a bad diet.
A chronic high-fat diet is thought to desensitize the brain to the feeling of satisfaction that one normally gets from a meal, causing a person to overeat in order to achieve the same high again. New research published today (August 15) in Science, however, suggests that this desensitization actually begins in the gut itself, where production of a satiety factor, which normally tells the brain to stop eating, becomes dialed down by the repeated intake of high-fat food.
“It’s really fantastic work,” said Paul Kenny, a professor of molecular therapeutics at The Scripps Research Institute in Jupiter, Florida, who was not involved in the study. “It could be a so-called missing link between gut and brain signaling, which has been something of a mystery.”
While pork belly, ice cream, and other high-fat foods produce an endorphin response in the brain when they hit the taste buds, according to Kenny, the gut also sends signals directly to the brain to control our feeding behavior. Indeed, mice nourished via gastric feeding tubes, which bypass the mouth, exhibit a surge in dopamine—a neurotransmitter promoting reinforcement in the brain’s reward circuitry—similar to that experienced by those eating normally.
This dopamine surge occurs in response to feeding in both mice and humans. But evidence suggests that dopamine signaling in the brain is deficient in obese people. Ivan de Araujo, a professor of psychiatry at the Yale School of Medicine, has now discovered that obese mice on a chronic high-fat diet also have a muted dopamine response when receiving fatty food via a direct tube to their stomachs.
To determine the nature of the dopamine-regulating signal emanating from the gut, Araujo and his team searched for possible candidates. “When you look at animals chronically exposed to high-fat foods, you see high levels of almost every circulating factor—leptin, insulin, triglycerides, glucose, et cetera,” he said. But one class of signaling molecule is suppressed. Of these, Araujo’s primary candidate was oleoylethanolamide. Not only is the factor produced by intestinal cells in response to food, he said, but during chronic high-fat exposure, “the suppression levels seemed to somehow match the suppression that we saw in dopamine release.”
Araujo confirmed oleoylethanol’s dopamine-regulating ability in mice by administering the factor via a catheter to the tissues surrounding their guts. “We discovered that by restoring the baseline level of [oleoylethanolamide] in the gut … the high-fat fed animals started having dopamine responses that were indistinguishable from their lean counterparts.”
The team also found that oleoylethanolamide’s effect on dopamine was transmitted via the vagus nerve, which runs between the brain and abdomen, and was dependent on its interaction with a transcription factor called PPAR-a.
Oleoylethanolamide levels are also reduced in fasting animals and increase in response to eating, communicating with the brain to stop further consumption once the belly is full. Indeed, oleoylethanolamide is a known satiety factor. Therefore, when chronic consumption of high-fat food diminishes its production, the satisfaction signal is not achieved, and the brain is essentially “blind to the presence of calories in the gut,” said Araujo, and thus demands more food.
It is not clear why a chronic high-fat diet suppresses the production of oleoylethanolamide. But once the vicious cycle starts, it is hard to break because the brain is receiving its information subconsciously, said Daniele Piomelli, a professor at the University of California, Irvine, and director of drug discovery and development at the Italian Institute of Technology in Genoa.
“We eat what we like, and we think we are conscious of what we like, but I think what this [paper] and others are indicating is that there is a deeper, darker side to liking—a side that we’re not aware of,” Piomelli said. “Because it is an innate drive, you can not control it.” Put another way, even if you could trick your taste buds into enjoying low-fat yogurt, you’re unlikely to trick your gut.
The good news, however, is that “there is no permanent impairment in the [animals’] dopamine levels,” Araujo said. This suggests that if drugs could be designed to regulate the oleoylethanolamide–to-PPAR-a pathway in the gut, Kenny added, it could have “a huge impact on people’s ability to control their appetite.”
A sleepless night makes us more likely to reach for doughnuts or pizza than for whole grains and leafy green vegetables, suggests a new study from UC Berkeley that examines the brain regions that control food choices. The findings shed new light on the link between poor sleep and obesity.
Using functional magnetic resonance imaging (fMRI), UC Berkeley researchers scanned the brains of 23 healthy young adults, first after a normal night’s sleep and next, after a sleepless night. They found impaired activity in the sleep-deprived brain’s frontal lobe, which governs complex decision-making, but increased activity in deeper brain centers that respond to rewards. Moreover, the participants favored unhealthy snack and junk foods when they were sleep deprived.
“What we have discovered is that high-level brain regions required for complex judgments and decisions become blunted by a lack of sleep, while more primal brain structures that control motivation and desire are amplified,” said Matthew Walker, a UC Berkeley professor of psychology and neuroscience and senior author of the study published today (Tuesday, Aug. 6) in the journal Nature Communications.
Moreover, he added, “high-calorie foods also became significantly more desirable when participants were sleep-deprived. This combination of altered brain activity and decision-making may help explain why people who sleep less also tend to be overweight or obese.”
Previous studies have linked poor sleep to greater appetites, particularly for sweet and salty foods, but the latest findings provide a specific brain mechanism explaining why food choices change for the worse following a sleepless night, Walker said.
“These results shed light on how the brain becomes impaired by sleep deprivation, leading to the selection of more unhealthy foods and, ultimately, higher rates of obesity,” said Stephanie Greer, a doctoral student in Walker’s Sleep and Neuroimaging Laboratory and lead author of the paper. Another co-author of the study is Andrea Goldstein, also a doctoral student in Walker’s lab.
In this newest study, researchers measured brain activity as participants viewed a series of 80 food images that ranged from high-to low-calorie and healthy and unhealthy, and rated their desire for each of the items. As an incentive, they were given the food they most craved after the MRI scan.
Food choices presented in the experiment ranged from fruits and vegetables, such as strawberries, apples and carrots, to high-calorie burgers, pizza and doughnuts. The latter are examples of the more popular choices following a sleepless night.
On a positive note, Walker said, the findings indicate that “getting enough sleep is one factor that can help promote weight control by priming the brain mechanisms governing appropriate food choices.”
In the constant cross talk between our brain and our gut, two gut hormones are already known to tell the brain when we have had enough to eat. New research suggests that boosting levels of these hormones simultaneously may be an effective new weapon in the fight against obesity.
Dr Shu Lin, Dr Yan-Chuan Shi and Professor Herbert Herzog, from Sydney’s Garvan Institute of Medical Research, have shown that when mice are injected with PYY3-36 and PP, they eat less, gain less fat, and tend not to develop insulin-resistance, a precursor to diabetes. At the same time, the researchers have shown that the hormones stimulate different nerve pathways, ultimately, however, affecting complementary brain regions. Their findings are now published online in the journal .
While the double-barreled approach may seem like a no-brainer, the strongly enhanced effect seen was by no means inevitable. In the complex world of neuroscience, two plus two does not always make four.
Drug companies are in the process of conducting pre-clinical trials to examine the separate effects of boosting the hormones PYY3-36 and PP. Until now, there is no research to indicate the detailed molecular interactions that might occur when they are boosted in tandem.
When used together, the hormones independently, yet with combined force, reduce the amount of neuropeptide Y (NPY) produced by the brain, a powerful neurotransmitter that affects a variety of things including appetite, mood, heart rate, temperature and energy levels.
Each hormone also communicates with a different part of the arcuate nucleus in the hypothalamus, a region of the brain where signals can cross the normally impermeable blood / brain barrier. The stimulated regions then produce other neuronal signals deep within the hypothalamus, bringing about a powerful combined effect.
“There are many factors that influence appetite control – and we now realise that there won’t be a single molecular target, or a single drug, that will be effective,” said Dr Yan-Chuan Shi.
“It will be important for drug companies to try different combinations of targets, to see which combinations are most potent, and at the same time have no side effects, or at least minimal side effects.”
“At the moment, the only effective tool against obesity is surgery. Drug companies have so far failed to produce an effective drug without unacceptable side effects, such as mood disorders, nausea or cardiovascular problems.”
Researchers with the UC Davis MIND Institute and Agilent Laboratories have found that Prader-Willi syndrome — a genetic disorder best known for causing an insatiable appetite that can lead to morbid obesity — is associated with the loss of non-coding RNAs, resulting in the dysregulation of circadian and metabolic genes, accelerated energy expenditure and metabolic differences during sleep.
The research was led by Janine LaSalle, a professor in the UC Davis Department of Medical Microbiology and Immunology who is affiliated with the MIND Institute. It is published online in Human Molecular Genetics.
“Prader-Willi syndrome children do not sleep as well at night and have daytime sleepiness,” LaSalle said. “Parents have to lock up their pantries because the kids are rummaging for food in the middle of the night, even breaking into their neighbors’ houses to eat.”
The study found that these behaviors are rooted in the loss of a long non-coding RNA that functions to balance energy expenditure in the brain during sleep. The finding could have a profound effect on how clinicians treat children with Prader-Willi, as well as point the way to new, innovative therapies, LaSalle said.
The leading cause of morbid obesity among children in the United States, Prader-Willi involves a complex, and sometimes contradictory, array of symptoms. Shortly after birth children with Prader-Willi experience failure to thrive. Yet after they begin to feed themselves, they have difficulty sleeping and insatiable appetites that lead to obesity if their diets are not carefully monitored.
The current study was conducted in a mouse model of Prader-Willi syndrome. It found that mice engineered with the loss of a long non-coding RNA showed altered energy use and metabolic differences during sleep.
Prader-Willi has been traced to a specific region on chromosome 15 (SNORD116), which produces RNAs that regulate gene expression, rather than coding for proteins. When functioning normally, SNORD116 produces small nucleolar (sno) RNAs and a long non-coding RNA (116HG), as well as a third non-coding RNA implicated in a related disorder, Angelman syndrome. The 116HG long non-coding RNA forms a cloud inside neuronal nuclei that associates with proteins and genes regulating diurnal metabolism in the brain, LaSalle said.
“We thought the cloud would be activating transcription, but in fact it was doing the opposite,” she said. “Most of the genes were dampened by the cloud. This long non-coding RNA was acting as a decoy, pulling the active transcription factors away from genes and keeping them from being expressed.”
As a result, losing snoRNAs and 116HG causes a chain reaction, eliminating the RNA cloud and allowing circadian and metabolic genes to get turned on during sleep periods, when they should be dampened down. This underlies a complex cycle in which the RNA cloud grew during sleep periods (daytime for nocturnal mice), turning down genes associated with energy use, and receded during waking periods, allowing these genes to be expressed. Mice without the 116HG gene lacked the benefit of this neuronal cloud, causing greater energy expenditure during sleep.
The researchers said that the work provides a clearer picture of why children with Prader-Willi syndrome can’t sleep or feel satiated and may change therapeutic approaches. For example, many such children have been treated with growth hormone because of short stature, but this actually may boost other aspects of the disease.
“People had thought the kids weren’t sleeping at night because of the sleep apnea caused by obesity,” said LaSalle. “What this study shows is that the diurnal metabolism is central to the disorder, and that the obesity may be as a result of that. If you can work with that, you could improve therapies, for example figuring out the best times to administer medications.”
Memory improves in older, overweight women after they lose weight by dieting, and their brain activity actually changes in the regions of the brain that are important for memory tasks, a new study finds. The results were presented at The Endocrine Society’s 95th Annual Meeting in San Francisco.
“Our findings suggest that obesity-associated impairments in memory function are reversible, adding incentive for weight loss,” said lead author Andreas Pettersson, MD, a PhD student at Umea University, Umea, Sweden.
Previous research has shown that obese people have impaired episodic memory, the memory of events that happen throughout one’s life.
Pettersson and co-workers performed their study to determine whether weight loss would improve memory and whether improved memory correlated with changes in relevant brain activity. A special type of brain imaging called functional magnetic resonance imaging (functional MRI) allowed them to see brain activity while the subjects performed a memory test.
The researchers randomly assigned 20 overweight, postmenopausal women (average age, 61) to one of two healthy weight loss diets for six months. Nine women used the Paleolithic diet, also called the Caveman diet, which was composed of 30 percent protein; 30 percent carbohydrates, or “carbs”; and 40 percent unsaturated fats. The other 11 women followed the Nordic Nutrition Recommendations of a diet containing 15 percent protein, 55 percent carbs and 30 percent fats.
Before and after the diet, the investigators measured the women’s body mass index (BMI, a measure of weight and height) and body fat composition. They also tested the subjects’ episodic memory by instructing them to memorize unknown pairs of faces and names presented on a screen during functional MRI. The name for this process of creating new memory is “encoding.” Later, the women again saw the facial images along with three letters. Their memory retrieval task, during functional MRI, was to indicate the correct letter that corresponded to the first letter of the name linked to the face.
Because the two dietary groups did not differ in body measurements and functional MRI data, their data were combined and analyzed as one group. The group’s average BMI decreased from 32.1 before the diet to 29.2 (below the cutoff for obesity) after six months of dieting, and their average weight dropped from 188.9 pounds (85 kilograms) to 171.3 pounds (77.1 kilograms), the authors reported. This study was part of a larger, diet-focused study funded by the Swedish Research Council and the Swedish Heart-Lung Foundation.
Memory performance improved after weight loss, and Pettersson said the brain-activity pattern during memory testing reflected this improvement. After weight loss, brain activity reportedly increased during memory encoding in the brain regions that are important for identification and matching of faces. In addition, brain activity decreased after weight loss in the regions that are associated with retrieval of episodic memories, which Pettersson said indicates more efficient retrieval.
“The altered brain activity after weight loss suggests that the brain becomes more active while storing new memories and therefore needs fewer brain resources to recollect stored information,” he said.
PET study led by Stony Brook Professor indicates that overeating and weight gain contributing to onset of diabetes could be related to a deficit in reward circuits in the brain
Using positron emission tomography (PET) imaging of the brain, researchers have identified a sweet spot that operates in a disorderly way when simple sugars are introduced to people with insulin resistance, a precursor to type 2 diabetes. For those who have the metabolic syndrome, a sugar drink resulted in a lower-than-normal release of the chemical dopamine in a major pleasure center of the brain. This chemical response may be indicative of a deficient reward system, which could potentially be setting the stage for insulin resistance. This research could revolutionize the medical community’s understanding of how food-reward signaling contributes to obesity, according to a study presented at the Society of Nuclear Medicine and Molecular Imaging’s 2013 Annual Meeting.
"Insulin resistance is a significant contributor to obesity and diabetes," said Gene-Jack Wang, MD, lead author of the study and Professor of Radiology at Stony Brook University and researcher at the U.S. Department of Energy’s Brookhaven National Laboratory in Upton, N.Y. "A better understanding of the cerebral mechanisms underlying abnormal eating behaviors with insulin resistance would help in the development of interventions to counteract the deterioration caused by overeating and subsequent obesity. We suggest that insulin resistance and its association with less dopamine release in a central brain reward region might promote overeating to compensate for this deficit."
An estimated one-third of Americans are obese, according to the U.S. Centers for Disease Control and Prevention. The American Diabetes Association estimates that about 26 million Americans are living with diabetes and another 79 million are thought to be prediabetic, including those with insulin resistance.
The tendency to overeat may be caused by a complex biochemical relationship, as evidenced by preliminary research with rodents. Dr. Wang’s research marks the first clinical study of its kind with human subjects.
"Animal studies indicated that increased insulin resistance precedes the lack of control associated with pathological overeating," said Wang. "They also showed that sugar ingestion releases dopamine in brain regions associated with reward. However, the central mechanism that contributes to insulin resistance, pathological eating and weight gain is unknown."
He continued, “In this study we were able to confirm an abnormal dopamine response to glucose ingestion in the nucleus accumbens, where much of the brain’s reward circuitry is located. This may be the link we have been looking for between insulin resistance and obesity. To test this, we gave a glucose drink to an insulin-sensitive control group and an insulin-resistant group of individuals and we compared the release of dopamine in the brain reward center using PET.”
In this study, a total of 19 participants-including 11 healthy controls and eight insulin-resistant subjects-consumed a glucose drink and, on a separate day, an artificially sweetened drink containing sucralose. After each drink, PET imaging with C-11 raclopride-which binds to dopamine receptors-was performed. Researchers mapped lit-up areas of the brain and then gauged striatal dopamine receptor availability (which is inversely related to the amount of natural dopamine present in the brain). These results were matched with an evaluation in which patients were asked to document their eating behavior to assess any abnormal patterns in their day-to-day lives. Results showed agreement in receptor availability between insulin-resistant and healthy controls after ingestion of sucralose. However, after patients drank the sugary glucose, those who were insulin-resistant and had signs of disorderly eating were found to have remarkably lower natural dopamine release in response to glucose ingestion when compared with the insulin-sensitive control subjects.
"This study could help develop interventions, i.e., medication and lifestyle modification, for early-stage insulin-resistant subjects to counteract the deterioration that leads to obesity and/or diabetes," said Wang. "The findings set a path for future clinical studies using molecular imaging methods to assess the link of peripheral hormones with brain neurotransmitter systems and their association with eating behaviors."
Findings may have implications for treating compulsive behavior associated with psychiatric disease and eating disorders
What started as an experiment to probe brain circuits involved in compulsive behavior has revealed a surprising connection with obesity.
The University of Iowa-led researchers bred mice missing a gene known to cause obesity, and suspected to also be involved in compulsive behavior, with a genetic mouse model of compulsive grooming. The unexpected result was offspring that were neither compulsive groomers nor obese.
The study, published the week of June 10 in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), suggests that the brain circuits that control obsessive-compulsive behavior are intertwined with circuits that control food intake and body weight. The findings have implications for treating compulsive behavior, which is associated with many forms of psychiatric disease, including obsessive-compulsive disorder (OCD), Tourette syndrome, and eating disorders.
UI neuro-psychiatrists Michael Lutter, M.D., Ph.D. and Andrew Pieper, M.D., Ph.D. led the study. The team also included researchers from Stanford University School of Medicine, University of Texas Southwestern Medical Center, Beth Israel Deaconess Medical Center, and Harvard Medical School.
Lutter, an assistant professor of psychiatry, and Pieper, an associate professor of psychiatry and neurology at the UI Carver College of Medicine, both recently arrived at the UI and use mouse models in their laboratories to study human disorders and conditions.
Pieper is interested in compulsive behavior. His mouse model of compulsivity lacks a brain protein called SAPAP3. These mice groom themselves excessively to the point of lesioning their skin, and their compulsive behavior can be effectively treated by fluoxetine, a drug that is commonly used to treat OCD in people.
Lutter works with a mouse that genetically mimics an inherited form of human obesity. This mouse lacks a brain protein known a MC4R. Mutations in the MC4R gene are the most common single-gene cause of morbid obesity and over-eating in people.
“I study MC4R signaling pathways and their involvement in the development of obesity,” Lutter explains. “I’m also interested in how these same molecules affect mood and anxiety and reward, because it’s known that there is a connection between depression and anxiety and development of obesity.”
An old study hinted that in addition to its role in food intake and obesity, MC4R might also play a role in compulsive behavior, which got Lutter and Pieper thinking of ways to test the possible interaction.
"We knew in one mouse you could stimulate excessive grooming through this MC4R pathway and in another mouse a different pathway (SAPAP3) caused compulsive grooming," Lutter says. "So, we decided to breed the two mice together to see if it would have an effect on compulsive grooming."
The experiment proved their original hypothesis—knocking out the MC4R protein in the OCD mouse normalized grooming behavior in the animals. In addition, chemically blocking MC4R in the OCD mice also eliminated compulsive grooming. The rescued behavior is mirrored by normalization of a particular pattern of brain cell communication linked to compulsive behavior.
However, the breeding experiment revealed another totally unexpected result. Loss of the SAPAP3 protein from the mice that were obese due to lack of MC4R produced mice of normal weight.
"We had this other, completely shocking finding—we completely rescued body weight and food intake in the double null mouse," Lutter says. "So, not only were we affecting the brain regions involved in grooming and behavior, but we also affected the brain regions involved in food intake and body weight."
Although obesity and obsessive-compulsive behavior may seem unrelated, Lutter suggests that the connection may be rooted in the evolutionary need to eat safe, clean food in times of a food abundance, and to lessen this drive when food is scarce.
"Food safety has been an issue through the entire course of human evolution—refrigeration is a relatively recent invention," he says. "Obsessive behavior, or fear of contamination, may be an evolutionary protection against eating rotten food."
Oils and fats have lots of calories and nutrients but they also spoil much more easily than less nutrient- and calorie-dense foods like potatoes, onions, or apples.
"I think this circuit that we have uncovered is probably involved in determining whether or not people should eat calorically dense foods," he says.
Lutter suggests that slight perturbations in this system might lead, on one hand, to disorders that link anxiety and obsessive behavior to limited food selection or intake, such as anorexia nervosa, Tourette syndrome, or OCD, and on the other hand, to obesity, where people over-consume high-fat foods and may have decreased obsessive behavior and anxiety.
“The next step will be to determine how these two pathways communicate with one another, in hopes of identifying new ways to develop drugs to treat either of these disorders,” says Pieper.