Posts tagged anorexia
Posts tagged anorexia
Eating disorders like anorexia nervosa and bulimia often run in families, but identifying specific genes that increase a person’s risk for these complex disorders has proved difficult.
Now scientists from the University of Iowa and University of Texas Southwestern Medical Center have discovered—by studying the genetics of two families severely affected by eating disorders—two gene mutations, one in each family, that are associated with increased risk of developing eating disorders.
Moreover, the new study shows that the two genes interact in the same signaling pathway in the brain, and that the two mutations produce the same biological effect. The findings suggest that this pathway might represent a new target for understanding and potentially treating eating disorders.
"If you’re considering two randomly discovered genes, the chance that they will interact is small. But, what really sealed the deal for us that the association was real was that the mutations have the same effect," says Michael Lutter, UI assistant professor of psychiatry and senior author of the study.
Overall, the study, published Oct. 8 in the Journal of Clinical Investigation, suggests that mutations that decrease the activity of a transcription factor—a protein that turns on the expression of other genes—called estrogen-related receptor alpha (ESRRA) increase the risk of eating disorders.
The challenge of finding genes for complex diseases
Anorexia nervosa and bulimia nervosa are fairly common, especially among women. They affect between 1 and 3 percent of women. They also are among the most lethal of all psychiatric diseases; about 1 in 1,000 women will die from anorexia.
Finding genes associated with complex diseases like eating disorders is challenging. Scientists can analyze the genetics of thousands of people and use statistics to find common, low-risk gene variations, the accumulation of which causes complex disorders from psychiatric conditions like eating disorders to conditions like heart disease or obesity.
On the other end of the spectrum are very rare gene variants, which confer an almost 100 percent risk of getting the disease. To track down these variants, researchers turn to large families that are severely affected by an illness.
Lutter and his colleagues were able to work with two such families to identify the two new genes associated with eating disorders.
"It’s basically a matter of finding out what the people with the disorder share in common that people without the disease don’t have," Lutter explains. "From a theoretical perspective, it’s straightforward. But the difficulty comes in having a large enough group to find these rare genes. You have to have large families to get the statistical power."
In the new study, 20 members from three generations of one family (10 affected individuals and 10 unaffected), and eight members of a second family (six affected and two unaffected) were analyzed.
Two genes, one pathway
The gene discovered in the larger family was ESRRA, a transcription factor that turns on the expression of other genes. The mutation associated with eating disorders decreases ESSRA activity.
The gene found in the second family is a transcriptional repressor called histone deacetylase 4 (HDAC4), which turns off transcription factors, including ESRRA. This mutation is unusual in the sense that it increases the gene’s activity—most mutations decrease or destroy a gene’s activity.
Importantly, the team also found that the two affected proteins interacted with one another; HDAC4 binds to ESRRA and inhibits it.
"The fact that the HDAC4 mutation happens to increase the gene activity and happens to increase its ability to repress the ESSRA protein we found in the other family was just beyond coincidence," Lutter says.
The two genes are already known to be involved in metabolic pathways in muscle and fat tissue. They also are both regulated by exercise.
In the brain, HDAC4 is very important for regulating genes that form connections between neurons. However, there’s almost nothing known about ESRRA in the brain, although it is expressed in many brain regions that are disrupted in anorexia.
Lutter and his colleagues plan to study the role of these genes in mice and in cultured neurons to find out exactly what they are doing in the brain. They will also look for ways to modify the genes’ activity, with the long-term goal of finding small molecules that might be developed into therapies for eating disorders.
They also plan to study patients with eating disorders and see if other genes associated with the ESSRA/HDAC4 brain pathway are affected in humans.
In a world first, a team of researchers at the Krembil Neuroscience Centre and the University Health Network have shown that Deep Brain Stimulation (DBS) in patients with chronic, severe and treatment-resistant Anorexia Nervosa (anorexia) helps some patients achieve and maintain improvements in body weight, mood, and anxiety.
The results of this trial, entitled Deep Brain Stimulation of the Subcallosal Cingulate Area for Treatment-Refractory Anorexia Nervosa: A Phase I Pilot Trial, are published in the medical journal The Lancet. The study is a collaboration between lead author Dr. Nir Lipsman a neurosurgery resident at the University of Toronto and PhD student at the Krembil Neuroscience Centre; Dr. Andres Lozano, a neurosurgeon, at the Krembil Neuroscience Centre of Toronto Western Hospital and a professor and chairman of neurosurgery at the University of Toronto, whose research lab was instrumental in conducting the DBS research; and Dr. Blake Woodside, medical director of Canada’s largest eating disorders program at Toronto General Hospital and a professor of psychiatry at the University of Toronto.
The phase one safety trial investigated the procedure in six patients who would likely continue with a chronic illness and/or die a premature death because of the severity of their condition. The study’s participants had an average age of 38, and a mean duration of illness of 18 years. In addition to the anorexia, all patients, except one, also suffered from psychiatric conditions such as major depressive disorder and obsessive-compulsive disorder. At the time of the study, all patients currently, or had previously, suffered multiple medical complications related to their anorexia – altogether, the six patients had a history of close to 50 hospitalizations during their illnesses.
Study participants were treated with Deep Brain Stimulation (DBS), a neurosurgical procedure that moderates the activity of dysfunctional brain circuits. Neuroimaging has shown that there are both structural and functional differences between anorexia patients and healthy controls in brain circuits which regulate mood, anxiety, reward and body-perception.
Patients were awake when they underwent the procedure which implanted electrodes into a specific part of the brain involved with emotion, and found to be highly important in disorders such as depression. During the procedure, each electrode contact was stimulated to look for patient response of changes in mood, anxiety or adverse effects. Once implanted, the electrodes were connected to an implanted pulse generator below the right clavicle, much like a heart pacemaker.
Testing of patients was repeated at one, three, and six-month intervals after activation of the pulse generator device. After a nine-month period following surgery, the team observed that three of the six patients had achieved weight gain which was defined as a body-mass index (BMI) significantly greater than ever experienced by the patients. For these patients, this was the longest period of sustained weight gain since the onset of their illness. Furthermore, four of the six patients also experienced simultaneous changes in mood, anxiety, control over emotional responses, urges to binge and purge and other symptoms related to anorexia, such as obsessions and compulsions. As a result of these changes, two of these patients completed an inpatient eating disorders program for the first time in the course of their illness.
“We are truly ushering in a new of era of understanding of the brain and the role it can play in certain neurological disorders,” says Dr. Lozano. “By pinpointing and correcting the precise circuits in the brain associated with the symptoms of some of these conditions, we are finding additional options to treat these illnesses.”
While the treatment is still considered experimental, it is believed to work by stimulating a specific area of the brain to reverse abnormalities linked to mood, anxiety, emotional control, obsessions and compulsions all of which are common in anorexia. In some cases after surgery, patients are then able to complete previously unsuccessful treatments for the disease. The research may not only provide an additional therapy option for these patients in the future, but also furthers practitioners’ understanding of anorexia and the factors that cause it to be persistent.
“There is an urgent need for additional therapies to help those suffering from severe anorexia,” says Dr. Woodside. “Eating disorders have the highest death rate of any mental illness and more and more women are dying from anorexia. Any treatment that could potentially change the natural course of this illness is not just offering hope but saving the lives for those that suffer from the extreme form of this condition.”
A leading international expert in the field of DBS research, Dr. Lozano has been exploring the potential of DBS to treat a variety of conditions. Most recently, his team began the first ever DBS trial of patients with early Alzheimer’s disease, and showed that stimulation may help improve memory. This trial has now entered its second phase and expanded to medical centres in the United States.
A new study published in Social Cognitive and Affective Neuroscience by researchers at the Center for BrainHealth at UT Dallas and UT Southwestern found brain-based differences in how women with and without anorexia perceive themselves. The findings shed light on how brain pathways function in ill and fully recovered individuals who have had anorexia nervosa.
The abuse of methamphetamine can have significant harmful side effects in humans. It burdens the body with toxic metabolic byproducts and weakens the heart, muscles and bones. It alters energy metabolism in the brain and kills brain cells.
Previous studies have shown that the fruit fly Drosophila melanogaster is a good model organism for studying the effects of methamphetamine on the body and brain. Researchers have found that meth exposure has similar toxicological effects in fruit flies and in humans and other mammals.
May 14, 2012
Why does one person become anorexic and another obese? A study recently published by a University of Colorado School of Medicine researcher shows that reward circuits in the brain are sensitized in anorexic women and desensitized in obese women. The findings also suggest that eating behavior is related to brain dopamine pathways involved in addictions.
Guido Frank, MD, assistant professor director of the Developmental Brain Research Program at the CU School of Medicine and his colleagues used functional magnetic resonance imaging (fMRI) to examine brain activity in 63 women who were either anorexic or obese. Scientists compared them to women considered “normal” weight. The participants were visually conditioned to associate certain shapes with either a sweet or a non-sweet solution and then received the taste solutions expectedly or unexpectedly. This task has been associated with brain dopamine function in the past.
The authors found that during these fMRI sessions, an unexpected sweet-tasting solution resulted in increased neural activation of reward systems in the anorexic patients and diminished activation in obese individuals. In rodents, food restriction and weight loss have been associated with greater dopamine-related reward responses in the brain.
"It is clear that in humans the brain’s reward system helps to regulate food intake" said Frank. "The specific role of these networks in eating disorders such as anorexia nervosa and, conversely, obesity, remains unclear.”
Scientists agree that more research is needed in this area. The study was published in Neuropsychopharmacology.
Provided by University of Colorado Denver