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A molecule that puts the brakes on appetite
“Dry cleaning” effect — research shows how mice, and people, work on autopilot
Et cetera
Biomarker for lung cancer risk
Yale paper among best of 2008
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A molecule that puts the brakes on appetite
Yale scientists find a family of phospholipids that curb the desire to eat in rats and mice.
That heaping pile of golden crisp French fries looks delectable, but polishing off the plate may be a tall order. New research from Yale scientists suggests that a family of phospholipids tells the brain when an animal has had its fill of fat—findings that help explain the physiologic mechanism that wards off a deep-fried feeding frenzy. And these phospholipids, called N-acylphosphatidylethanolamines, or NAPEs, may hold the key to new treatments for obesity.
The human body has several built-in systems that keep us from stuffing ourselves silly. Leptin, for example, tells the brain to put the brakes on eating when fat stores are abundant. Now a team led by Gerald I. Shulman, M.D., Ph.D., the George R. Cowgill Professor of Physiological Chemistry, professor of medicine and of cellular and molecular physiology and a Howard Hughes Medical Institute investigator, has identified a new class of appetite-suppressing molecules—the NAPEs—that become synthesized in rats after a high-fat meal, as reported in November in the journal Cell.
The researchers teased apart the function of NAPEs by synthesizing the most physiologically abundant NAPE and injecting it into rodents. They found that the higher the concentration of the phospholipid, the less the rodents ate. Furthermore, like someone sitting back after a feast, the NAPE-injected mice lounged about and groomed themselves even though they ate only a mini-meal.
Shulman’s group discovered that NAPEs, like certain other chemicals that help to control appetite, exert their effects via the central nervous system. They appear to be synthesized in the small intestine after a high-fat meal but they then get dumped into the blood and lymphatic system, putting them on a fast track to the brain. When Shulman’s team injected nanomolar amounts of NAPE directly into rodent brains, it slashed the animals’ appetites by more than 50 percent and shut down the activity of NPY neurons, which stimulate appetite.
On a roll, the researchers decided to treat the rats with NAPE for five straight days. They found that the rodents ate 30 percent less food and shed a significant amount of weight.
The race is now on to see whether these rodent findings translate to humans. Shulman’s team is investigating NAPE regulation in humans following feeding, and the researchers soon plan to treat monkeys with NAPEs to observe the effects on appetite. Provided those studies pan out, Shulman is eager to see whether NAPEs can reduce food intake in humans. If they do, NAPEs could serve as the basis of novel appetite-suppressant or obesity-fighting drugs. “Obesity is a major health problem, and we have very few treatments available,” Shulman said. “We are always looking to better understand appetite regulation, and NAPEs may be a new physiological regulator of appetite.”
—Kara A. Nyberg
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“Dry cleaning” effect—research shows how mice, and people, work on autopilot
By watching mice navigate a custom-designed swimming pool, Christopher Pittenger, M.D., Ph.D., assistant professor of psychiatry, has discovered an ongoing competition between one part of the brain devoted to active seeking and another part devoted to mindless cruising. These two sections of the brain, his research shows, can inhibit each other, depending on the task at hand or, in this case, at paw. The competition, which likely occurs in people as well, may explain why it can be so hard to alter set routines, and could explain the power of such unwanted habits as drug addiction or obsessive-compulsive behaviors.
Pittenger’s study found that two parallel learning and memory systems that reside in different parts of the brain can block each other’s functions. The striatum powers up when—as if on autopilot—we embark on a well-known route like driving to work. The hippocampus comes into play when we need to think about where we’re going, as when we’re looking for a new address or detouring for an errand. The study found that when one system is impaired, the other is enhanced: in mice, injuring the striatum made the animals worse at locating a visual target in a water maze, but better at more active hippocampus-based navigational skills, and vice versa.
This reciprocal inhibition may explain the difficulty many people have in breaking from an entrenched routine. “This is why I cannot, for the life of me, remember to drop off my dry cleaning on the way to work,” said Pittenger, whose findings were published in October in Proceedings of the National Academy of Sciences.
“When you have driven the same route many times and are doing it on autopilot, it can be really difficult to change. If I’m not paying enough attention right at that moment, if I am thinking about something else, I just sail right on by.”
On a more serious note, the findings may also help explain the behavioral peculiarities seen with some brain diseases. Alzheimer disease, for example, destroys hippocampal function. That may be why many people with this disease fall back on old behaviors, like repeatedly returning to a previous address, thinking it is still home. Other diseases, including obsessive-compulsive disorder (OCD) and Parkinson disease, involve striatal malfunction. Pittenger’s new results emphasize that this striatal malfunction is likely to lead to changes in the function of the hippocampus, too, which may either compensate for or exacerbate the symptoms of the disease.
Understanding the connections between memory systems may offer new ways to treat serious behavioral problems. “A lot of psychiatric diseases are characterized by recurrent, maladaptive patterns of thought or behavior,” says Pittenger, who is also director of the Yale Obsessive-Compulsive Disorder Research Clinic. “People with OCD or drug addiction just keep doing the same thing and can’t seem to stop, no matter how hard they try.”
Treatment for OCD often includes cognitive behavioral therapy, which works by engaging a more reflective thinking mode to try to control automatic behaviors. Pittenger speculates that the process may work by recruiting one brain region to overcome an excess in the other. If so, it might be possible to develop drugs to make cognitive therapy more effective by enhancing or balancing the activities of the striatum or hippocampus.
It’s quite a leap from mice paddling in a pool to human disease, Pittenger said, but learning how basic normal memory systems work in animals is an important first step.
—Pat McCaffrey
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et cetera
Biomarker for lung cancer risk
A genetic variation could explain why some people have a greater risk of developing lung cancer, Yale scientists reported in the journal Cancer Research in October.
“Only 10 percent of smokers will develop lung cancer in their lifetime, and genetic testing to determine the population of smokers who are most predisposed to develop the disease is needed to help guide better evaluation for these people,” said Joanne B. Weidhaas, M.D., Ph.D., assistant professor of therapeutic radiology at Yale. She was senior author of the study, in collaboration with Frank Slack, Ph.D., associate professor of molecular, cellular and developmental biology.
“We looked for the effects of genetic variations within a human oncogene known to be affected by tiny RNA molecules called micro-RNAs,” said Slack, explaining their discovery of the biomarker. These variations, called single nucleotide polymorphisms, predicted a significant increase in non-small-cell lung cancer risk in people with a moderate smoking history as well as in nonsmokers.
—John Curtis
Yale paper among best of 2008
An article by Yale scientists on the formation of cell membranes has been named one of the top scientific papers of 2008 by the journal Nature.
The paper, published in Cell in March 2008, explored how cells shape their membranes into tubes, spheres and other curved structures that they need in order to move, communicate and reproduce. Scientists including Vinzenz M. Unger, Ph.D., associate professor of molecular biophysics and biochemistry, M.D./Ph.D. student Adam Frost and Pietro De Camilli, M.D., the Eugene Higgins Professor of Cell Biology and Neurobiology, established how banana-shaped proteins called F-BAR domains form curved scaffolds that allow cell membranes to assume those forms.
Using a combination of cryoelectron microscopy and cell biology experiments, the team found that F-BARs accumulate side by side on flat membranes until attractive forces cause them to turn onto their tips en masse and pull the now-curved membrane into shape.
—Peter Farley
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