Influencing Metabolism with Molecular Clock Genes
Researchers at Penn's School of Medicine have discovered that components of the internal molecular clock of mammals have an important role in governing the metabolism of sugars and fats within the body. They found in mice that two of the well-studied proteins in the clock control the ability of animals to recover from the fall in blood sugar that occurs in response to insulin.
The investigators, lead by Dr. Dan Rudic, research associate in the department of pharmacology and lead author on the current study, demonstrate a role for the circadian clock proteins, Bmal1 and Clock, in regulating the day-to-day levels of glucose in the blood. Suppressing the action of these molecules eliminates the diurnal variation in glucose and triglyceride levels. They also found that a mutated Clock gene protected mice from diabetes induced by a high-fat diet. Together these findings represent the first molecular insight into how timing of what we eat—via the clock—can influence metabolism. The findings appear in the November 2 issue of the online journal PLoS Biology.
The master molecular clock in mammals is located in the brain in an area called the suprachiasmatic nucleus, clusters of neurons in the hypothalamus. Many of our basic functions, including regulating body temperature and hormone levels, vary throughout the day and night. Some of these changes may relate to being asleep or awake and on the job, but others are under the control of a biochemical timepiece that sets and resets daily.
Over the last several years, researchers have begun to appreciate that the molecular components of the clock exist in most, if not all, tissues of the body. Some years ago, a team led by senior author Dr. Garret FitzGerald, chairman of Penn's department of pharmacology, discovered a molecular clock in the heart and blood vessels and described for the first time how the master clock in the brain could use a hormone to control such a peripheral clock.
During the course of the group's research they found that many metabolic genes were among the roughly 10 percent of genes that oscillate in activity in a 24-hour period. Food is also an important cue in directing the daily oscillations of metabolism and blood-sugar levels. As such, what you eat, as well as how much and when, all interact with this process.
What's more, the researchers found that a high-fat diet amplified the oscillation in blood sugar over a 24-hour period and that disabling the Clock gene markedly reduced this effect. How this works is as yet unclear, but the researchers think that the clock mediates the impact of a fatty diet.
Over time humans have moved from eating our fill at one sitting after the hunt to continuous availability of fast food. Nutritionists have long speculated that it might matter whether we "nibble" or "gorge" our calories, and that this makes a difference in how our bodies handle a high-fat diet.
Identifying Initial Sensor for p53 Tumor-Suppressing Pathway
DNA breaks from radiation, toxic chemicals, or other environmental causes occur routinely in cells and, unless promptly and properly repaired, can lead to cancer-causing mutations. When the breaks cannot be repaired, and the cell is vulnerable to becoming cancerous, critical backup protection governed by the p53 protein kicks in. This protein is the end of the line in a vital signaling cascade that triggers cells with fatally damaged DNA to self-destruct so that they cannot cause cancer.
Scientists know that in the majority of human cancers the p53 pathway has been disabled. Despite the crucial nature of the p53 tumor-suppressor pathway, the answer to a central question has evaded researchers for years: How is the p53 pathway alerted to the presence of DNA breaks in the cell in the first place? If p53 lies at the end of the line in this pathway, what molecule is at the front, and how does it do its job?
In a new study led by researchers at the Wistar Institute, the sensor protein that identifies DNA breaks and activates the p53 cell-death program has been identified. Additionally, structural analysis of the protein and its interactions with DNA has revealed the specific mechanism by which the protein detects the breaks. The study was published November 3 in the online edition of the journal Nature.
According to Dr. Thanos D. Halazonetis, professor in the gene expression and regulation program at the Wistar Institute and senior author on the Nature study, the protein, known as 53BP1, recognizes a molecular site usually hidden within the DNA-packaging structure called chromatin, which makes up our chromosomes. Chromatin consists of DNA coiled around the edges of molecules called histones to form disk-shaped entities called nucleosomes. The nucleosomes themselves, then, are tightly packed together—possibly like a stack of coins, Dr. Halazonetis suggests—to form the dense chromatin. When all is as it should be with the DNA, a target site for 53BP1 lies at the center of each of the stacked nucleosome disks and is not available for binding.
"But if you have a DNA break, you can imagine that the nucleosomes might unravel and the stacking of the nucleosomes fall apart, exposing the site that 53BP1 recognizes," Dr. Halazonetis says. "This is the model we are proposing for how cells sense the presence of DNA breaks to activate the p53 pathway."
Treating Adolescent Obsessive-Compulsive Disorder
According to current epidemiological data, approximately 1 in 200 young people suffer from obsessive-compulsive disorder (OCD). OCD patients‘obsess' about thoughts of bad things that can happen (obsessions) and perform repetitive, destructive actions (compulsions) as a means of dealing with those thoughts. Now, Penn's School of Medicine researchers, in conjunction with a team of researchers from Duke University Medical Center, have developed a scientifically conclusive treatment combination—using Cognitive Behavior Therapy (CBT) and commonly prescribed anti-depressant medication—to help pediatric patients overcome OCD. Their conclusions—based on a five-year study—may be found in the October 27 issue of the Journal of the American Medical Association (JAMA).
Dr. Edna B. Foa, professor of psychology in psychiatry; Director, Center for the Treatment and Study of Anxiety; and Co-Principal Investigator for Penn's component of ‘The PeAiatric OCD Treatment Study (POTS)' says, "This investigation shows that children diagnosed with OCD respond better to a combination of CBT and Zoloft as compared to placebo and either treatment alone. However, at the Penn site, children responded equally well to CBT alone and to the combined treatment." Zoloft (sertraline) is a commonly prescribed selective serotonin reuptake inhibitor (SSRI), which elicits its effects by increasing the activity of serotnin in the brain. CBT includes helping the children confront anxiety-evoking situations and refraining from performing compulsions in order to learn their fears are exaggerated or unrealistic. This is the first study to test the efficacy of combining the two treatments in pediatric patients.
The researchers found that 53.6 percent of the participants in the combination group (CBT plus sertraline) showed little or no symptoms by the end of their treatment. For those only given CBT, 39.3 percent of participants showed less severe OCD symptoms. Participants on sertraline alone saw 21.4 percent of their group with less severe OCD symptoms. Only 3.6 percent of those receiving the placebo responded with greatly reduced OCD symptoms.
Of the Penn patients, 64 percent of participants in both the CBT alone and combination group showed little or no symptoms by the end of treatment. "These findings suggest we must determine which treatment works best for individual patients, and at the same time, we need to teach therapists how best to conduct CBT. This study proves that the effective use of CBT alone, and a combination of CBT with an SSRI, will greatly improve the chance for decreasing the symptoms of OCD."
Participating in National Alzheimer's Disease Research
The clinical diagnosis of Alzheimer's Disease (AD) remains imprecise, especially in its initial stages, with a definitive diagnosis requiring an autopsy. While research conducted in the past 10 years has led to dramatic advances in understanding AD increasing evidence suggests that potential AD therapies are likely to be most effective early in the course of the disease. To that end, reliable diagnostic tests for the early detection of AD are needed to increase the likelihood of arresting memory impairments and other cognitive deficits, says Dr. John Q. Trojanowski, director of the Institute on Aging, and co-director of the Center for Neurodegenerative Disease Research and the Marian S. Ware Alzheimer Program at Penn's School of Medicine.
The National Institute on Aging (NIA)—in conjunction with other Federal agencies, private companies, and organizations—launched a $60 million, five-year public-private partnership, the Alzheimer's Disease Neuroimaging Initiative (ADNI). Its purpose is to test whether serial magnetic resonance imaging, positron emission tomography, other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease.
The study could help researchers and clinicians develop new treatments and monitor their effectiveness, as well as lessen the time and cost of clinical trials. The project is the most comprehensive effort to date to find neuroimaging and other biomarkers for the cognitive changes associated with MCI and AD.
Within the Alzheimer's Disease Neuroimaging Initiative, the Penn Biomarker Core—led by Dr. Trojanowski—will collect biological samples from normal individuals and AD patients followed in the study in order to develop diagnostic laboratory tests for the early diagnosis of AD. The identification of informative AD biomarkers (chemicals and other biological substances) and the development of laboratory tests to measure these biomarkers in blood, urine, or cerebrospinal fluid could substantially improve methods for the early diagnosis of AD, in concert with imaging data.
For more information on the study contact the Alzheimer's Disease Education and Referral (ADEAR) Center at 1-800-438-4380.
Almanac, Vol. 51, No. 11, November 9, 2004