Study Reveals How Brain Controls Eating in Normal RatsA study by HMS researchers shows how the fat hormone leptin works in the brain to trigger the nerve cells that control eating. The study adds important details about how leptin, which is released into the bloodstream from fat, may control the cognitive aspects of feeding behavior. The paper, by Carol Elias and her colleagues in endocrinology and neurology at Beth Israel Deaconess, appears in the August Neuron. "We're starting to understand the brain pathways underlying body weight regulation," says senior author Joel Elmquist, HMS assistant professor of neurology and medicine at BID. "This study directly links neurons that respond to the fat hormone leptin and critical populations of nerve cells that regulate feeding behavior." In the past several years, researchers in Elmquist's lab have combined genetic techniques with neuroanatomic methods to tease out the details of the neural pathways linking leptin to eating. Last year, postdoctoral fellow Elias and her colleagues identified the pathway between the two parts of the hypothalamus that apparently make this connection. (Elias is now an assistant professor of anatomy at the University of São Paulo, Brazil.) Using two genetic markers of leptin action and nerve cell activity, the researchers have shown that two distinctive groups of cells in one part of the hypothalamus respond in opposite ways to leptin. Specifically, they have shown these leptin-sensitive cells have hardwired connections to key cells in another region of the hypothalamus that control the urge to eat.
Researchers from Beth Israel Deaconess and HMS have shown how the fat hormone leptin works in the brain to trigger the nerve cells that control eating. In the medial hypothalamus, leptin activates "anorectic" nerve cells, which release appetite-suppressing neuropeptides (POMC and CART). At the same time, leptin inhibits another group of leptin-sensitive nerve cells, called "orexigenic," which release appetite-regulatory neuropeptides (NPY and AGRP). The two groups of leptin-sensitive cells send appetite-suppressing signals to key nerve cells in the lateral hypothalamus, thought to control several behaviors including feeding (ORX and MCH).
Drugs for Childhood Hyperactivity Not Linked To Later Addiction
Treatment for attention deficit hyperactivity disorder (ADHD) often involves the use of potent stimulants, most commonly Ritalin. The use of such stimulants and the prevalence of ADHD has led many to fear that treatment, as Joseph Biederman says, "could 'prime' children to become addicts in the future." However, work by Biederman, HMS professor of psychiatry at MGH, and colleagues may allay some of these fears. In an article in the August Pediatrics, they report that "children who are medically treated for ADHD have a smaller risk of drug abuse than those who are not treated." They came to this conclusion through a study that has followed a group of more than 500 children for four years. Within this group, the ADHD data came from males at least 15 years old at the start of the study—56 medicated ADHD participants, 19 non-medicated ADHD participants, and 137 non-ADHD participants. They found that while medicated ADHD males are not at a greater risk for future drug abuse, males who have ADHD but are not treated are three times as likely to abuse drugs. Though the study was small, preliminary, and needs to be repeated across multiple age groups and in females, the authors are hopeful that "these results should reassure the families of children receiving these therapies."
Women's Health:
When Less Fat Doesn't Help and When More Grain Does
There's both bad news and good news about diet and women's health this month from the Brigham and Women's Hospital-based Nurses' Health Study. One new article presents evidence against the hypothesis that eating a low-fat diet after breast cancer diagnosis could improve a woman's chances of survival. Another reports that women who consume plenty of whole grains could significantly reduce their risk for heart disease. In the breast cancer study, published in the September 1 Cancer, "We found that despite popular belief, eating a diet low in fat did not significantly improve a woman's chance of survival when diagnosed with breast cancer," said lead author Michelle Holmes, instructor in medicine at BWH and Cambridge Hospital. "Diet after diagnosis is very important to study," she noted, "because for a woman who has breast cancer, it is only diet after diagnosis that can be changed." Most prior studies have looked at diet before women were diagnosed with breast cancer, and some found that risk of death was modestly increased among those with the highest total fat intake. But earlier this year, Holmes and colleagues published another Nurses' Health Study report suggesting that women who consume lower levels of fat or avoid specific types of fat do not decrease their risk of breast cancer. Other aspects of a woman's diet may affect breast cancer survival more than fat, the researchers report in the new study. "We observed that a diet rich in proteins from poultry and dairy products, but not from red meat, may play a role in increasing survival of breast cancer patients," says Holmes. "In fact, there was an approximately 30 to 35 percent lower risk of death found among those who ate the most poultry and dairy products." In the heart disease study, researchers followed 75,521 women, ages 38 to 63, over a period of 10 years. Participants completed dietary questionnaires in 1984 and again in 1986 and 1990. During the 10-year follow-up period, 761 cases of coronary heart disease were documented. The authors found that women who consumed two to three servings of whole grains per day, from sources like whole wheat bread, popcorn, oatmeal, or brown rice, reduced their risk for heart disease by 27 percent. Most women should not find it difficult to eat this amount of whole grains, says co-author Meir Stampfer, associate professor of medicine at BWH's Channing Lab. "By simply choosing to make a sandwich with two slices of whole wheat bread instead of white, a woman will get the beneficial two servings of whole grains she needs to protect her heart," he said. The researchers found that women with high whole grain intake smoked less, exercised more, and were more likely to receive hormone replacement therapy. However, even after taking into account differences in lifestyle and dietary factors, they found that a higher intake of whole-grain foods was still associated with a lower risk of heart disease. The study is published in the Sept. 1 American Journal of Clinical Nutrition.
Endostatin Shown to Have Greater Potency, Different Action Than Believed
A team of researchers led by Bjorn Olsen, the Hersey professor of cell biology at HMS and professor of oral biology at HSDM, has revealed that the angiogenesis inhibitor endostatin halts the growth of human renal cell carcinoma in mice at doses 2,000 times lower than previously reported. The study, published in the August 16 EMBO Journal, also showed that in vitro, minute picomolar concentrations of endostatin inhibit endothelial cell migration induced by vascular endothelial growth factor (VEGF). Endothelial cell migration is a necessary step in angiogenesis. The apparent potency of the endostatins used in the study has "obvious implications for the design of future clinical trials in humans," the authors write. Furthermore, the promising anticancer properties of this protein do not appear to be dependent on exposure of its N-terminal zinc-binding region, as previously thought, or its heparin binding sites. The researchers expressed recombinant wild-type and various mutant forms of both human and mouse endostatins in human embryonic kidney cells. Both wild-type and mutant forms lacking the zinc-binding region inhibited endothelial cell migration. When these endostatins were injected around the site of human kidney carcinomas grown subcutaneously in nude mice, both wild-type and mutant forms slowed further growth and caused tumor regression. Olsen, first author Noriko Yamaguchi (who was a visiting assistant professor of cell biology), and their colleagues found that the inhibitory activity of endostatin on cellular migration is only successful if the migrating cells are exposed to endostatin before VEGF. The researchers hypothesize that endostatin interferes with one or more steps in the VEGF-induced migration while the growth factor may block endostatin's inhibitory mechanisms. —Brief by Lorene Leiter and Catherine Chu
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