Genetics: Receptors Discovered that Direct Rod Cell Development Special Report: Visa Woes Threaten Conduct of Science Neurology: Mutation Suggests Novel Signaling Mechanism in Brain Development Metabolism Kinase Pathway Seen to Regulate Urge to Eat Medical Education Fourth-years Make Matches, Favor Internal Medicine, Pediatrics Doctors Struggle with Complex Issues When a Patient is Dying HMOs May Improve Diabetes Care by Providing Home Monitors   Proceedings of the HMS Faculty Council Projects in Epidemiology, Nutrition Take Prizes at HSPH Poster Day Rabkin Fellows Announced HMS Dean's Community Service Awards Deadline Extended In Memoriam: Wayne Streilein   Practice Principles Have to Stand on Actual Data   Medical Records Hit Slow Going from Paper Trail to Digital Highway   Front Page

METABOLISM Kinase Pathway Seen to Regulate Urge to Eat Molecule Is Possible Target for Appetite-Suppressing Drugs For a person perusing a menu or a mouse facing a dish of lab chow, the decision of when and how much to eat is a matter of basic biology. Peaks and valleys in blood glucose and changes in hormones like insulin and leptin signal the brain when it is time to slide up to the table or to push back. When everything works as nature intended, finely tuned neural circuits located in the hypothalamus regulate eating and metabolic activity to maintain optimal body weight. Barbara Kahn (left), Yasuhiko Minokoshi, and their colleagues have identified the enzyme AMPK as a regulator of food intake and therefore a possible target for anti-obesity drugs. But the results of appetite dysregulation are all around in the form of a rapidly growing obesity epidemic. In research aimed at understanding the regulation of food intake, HMS scientists have identified an energy-sensing protein kinase that responds to eating, insulin, and leptin to control appetite in mice. The enzyme, AMP-activated protein kinase (AMPK), is highly active in the hypothalamus of hungry mice and decreases when the animals are fed. Decreasing AMPK activity by introducing a mutated form of the kinase into a mouse hypothalamus caused the animal to eat less and lose weight. "Our discovery that the AMPK pathway in the hypothalamus can integrate nutritional and hormonal signals regulating food intake opens up a novel avenue for development of appetite-controlling therapies," said Barbara Kahn, HMS professor of medicine at Beth Israel Deaconess Medical Center and senior author of the research paper, which appeared online in Nature on March 17. In individual cells from yeast to mammals, AMPK acts as a fuel gauge that tells the cell when its energy stores are full and when it is running on empty. When activated, AMPK phosphorylates and regulates a host of other cellular enzymes that control production of the high-energy molecule ATP. "We hypothesized that hypothalamic AMPK might work as a nutrient and energy sensor in animals, regulated by glucose and/or insulin, like in yeast," said Yasuhiko Minokoshi, a visiting scientist in Kahn's lab and first author on the Nature report. Minokoshi knew that the enzyme was widely expressed in neurons, and previous work from Kahn's lab had shown that the appetite-suppressing hormone leptin regulates AMPK in skeletal muscle. "Our discovery that the AMPK pathway in the hypothalamus can integrate nutritional and hormonal signals regulating food intake opens up a novel avenue for development of appetite-controlling therapies." --Barbara Kahn To test their idea, researchers withheld food from mice overnight, then offered them breakfast. After the animals had eaten their fill, the scientists checked the ability of AMPK from several regions of the hypothalamus to phosphorylate a substrate peptide. They found the enzyme was inhibited. To figure out if increases in leptin, insulin, or glucose were the cause, they gave the mice each substance individually and discovered that all three decreased the activity of hypothalamic AMPK. These experiments showed for the first time that nutrients and feeding-responsive hormones could cause changes in the activity of AMPK in the mouse brain. But the investigators wanted to know if changes in enzyme activity could drive eating behavior. To find out, they introduced mutated forms of AMPK into the hypothalamus using viral vectors. They were able to express two different mutated subunits of the enzyme, one that inhibited enzyme activity (dominant negative AMPK) and one that made AMPK constitutively active. They discovered that when AMPK was shut off by the dominant negative mutant, food intake and body weight decreased. Part of the reason was that reduced AMPK activity resulted in lower expression of brain peptides like NPY that normally stimulate eating behavior. Conversely, when AMPK was artificially turned on, the animals ate more and gained weight faster than normal counterparts. Increased AMPK activity resulted in higher levels of appetite stimulatory peptides in fasting mice. Finally, when the mice carrying constantly active AMPK were treated with leptin, they continued eating, mimicking the leptin resistance seen in many obese people. This evidence that AMPK sends leptin's appetite-suppressing signal suggests that inhibiting AMPK with a drug could be a useful strategy to overcome leptin resistance and suppress appetite for the treatment of obesity, said Kahn. --Pat McCaffrey