interesting abstract on serotonin

This is just interesting.FEB 11 2000 from Havard GENETICS Serotonin Tied to Worm's Eating Pattern Study Has Implications for Type II Diabetes, Other Human Diseases Gary Ruvkun does not claim, except perhaps tongue-in-cheek, that his favorite lab creatures actually get depressed, bulimic, or anorexic. He does say, however, that the tiny roundworms have a lot to offer in understanding how the neurotransmitter underlying these and other disorders controls the effects of food on appetite and metabolism. In the February 3 Nature, the HMS professor of genetics at Massachusetts General Hospital and his colleagues report that Caenorhabditis elegans worms devoid of serotonin have abnormalities in their eating behavior and metabolism. Gary Ruvkun uses the tiny worm C. elegans to untangle the neurohormonal control of eating and metabolism, and what this might mean for diseases such as Type II diabetes. The paper describes the first instance in which an animal has been engineered without any serotonin. Previous knockout experiments in mice have eliminated one type of serotonin receptor at a time. About a dozen receptor subtypes are known, so each of these strains lacks only a small percentage of serotonin's combined effects. The Harvard team's analysis suggests that serotonin is an evolutionarily ancient reward signal. Made in response to the presence of food, serotonin in turn regulates appetite. It also switches on two parallel neuroendocrine pathways�the insulin pathway and one headed by a distant relative of the transforming growth factor beta (TGF-beta) superfamily of proteins�whose end products converge to control decisions on whether the animal expends energy on reproduction and stays thin or shuts down procreation and instead stores fat. "Serotonin is the internal signal that tells the worm it is well-fed. Without it, the worm thinks it is starving even though it bathes in food," says Ruvkun. With previous work, this research is beginning to paint a coherent molecular picture of how food and the neurohormonal control of metabolism are connected in the worm, he adds. While Ruvkun is primarily interested in establishing molecular mechanisms and seeing to what degree they apply to higher animals, he says this work also has implications for human disease, especially Type II diabetes, and is already being adapted for drug screening purposes. A Jack of All Trades The current study supports a body of literature on serotonin in mammals, including humans. Serotonin is a multifarious substance, participating in the control of sleep, memory, learning, mood, body temperature, muscle contraction, even cardiovascular and other functions. Serotonin's link to eating first appeared as a side effect during clinical trials for the antidepressant Prozac in the early 1980s. Now, this selective serotonin reuptake inhibitor and other members of its class are sometimes prescribed to ease the binge-and-purge cycles in bulimia. Conversely, stimulant drugs treating attention deficit disorders can have unwanted appetite-suppressing side effects. The literature, however, is somewhat helter-skelter, says Ruvkun. Drug data are always difficult to interpret because drugs affecting serotonin have effects on related neurotransmitters as well. Another major source of serotonin data in mammals�knockout experiments in mice�produces cleaner data but also cannot yet establish clear molecular pathways in a system as complicated as the mammalian brain. This is true partly because researchers cannot tell how much serotonin signaling may be compensated through the remaining receptor types in any given mouse. Given these complexities, "it is all the more satisfying that our findings are so resonant with serotonin data from mammals," says Ruvkun. Eliminating Serotonin The project started with an analysis of the C. elegans genome. Ruvkun's former postdoc Ji Ying Sze�now at the University of California, Irvine�realized that the worm had only one gene for a key serotonin-producing enzyme. Knocking it out should therefore generate a serotonin-free animal. With help from co-author Martin Victor, a postdoc in the laboratory of HMS associate professor of pathology Yang Shi, Sze made such a mutant and analyzed it. The lack of serotonin threw the worm's metabolism out of whack in distinctive ways. For one, the mutants ate less. (Measuring worm appetite is easy: the scientist peers through a microscope and counts the pumping movements the worms make as they slurp in food�all day long.) For another, the worms stopped reproducing and, instead, stored large amounts of fat in their intestine. If growing fat while eating less makes no sense at first, it does once you consider how much energy a worm shunts toward reproduction. An adult hermaphrodite typically lays about 300 eggs in four days (see image). Each egg measures about five percent of an adult's size, meaning the worm generates�and expels�15 times its own weight in eggs. Quitting that frees up energy to get fat even on a meager diet, says Ruvkun. In doing so, the worm enters a hibernation stage called the dauer larvae, whose molecular control is being intensely studied. Worms usually enter this stage when food is scarce or in response to a pheromone they sense when the population density increases�much like bacteria shifting their metabolism as a way of hunkering down in hard times. When serotonin tells a roundworm that food is plentiful and times are good, the adult hermaphrodite will generate and lay�in four days�roughly 300 eggs (arrows), which together amount to 15 times the adult's body weight. Without serotonin, the worm "concludes" it is starving, regardless of how much food there is. It makes no eggs but instead stores copious amounts of fat (top image, black dots), suggesting that serotonin controls major decisions about metabolism and reproduction. Blazing Trails In the past three years, Ruvkun's and other labs have unraveled two neuroendocrine pathways that change as the animals enter the dauer stage. One is a signal transduction pathway for insulin, the other one for DAF-7, a worm homolog of the far-flung family of TGF-beta growth factors, which are involved in development and diabetes, among other things. Previous research had suggested that both pathways act in parallel in controlling reproductive and metabolic gene expression. The new paper places serotonin at the entry points to both those pathways, presenting a chain of molecular links for how serotonin reaches down to decisions on energy expenditure, eating, and reproduction. These pathways have encouraged speculation about the sources of Type II diabetes, a condition often preceded by obesity and insulin resistance. Ruvkun says he finds striking the fact that the pheromone inducing the dauer stage is a fatty acid. It inhibits DAF-7, thus turning down the pathway that is synergistic with insulin. Perhaps fatty acids in the blood of obese people do a similar thing, thus causing insulin resistance even though the insulin pathway per se works. Ruvkun hopes that serotonin pathways in the worm might yield valuable drug targets. Worms can be conveniently grown in microwell plates and are already being used in primary screens by a Belgian company that has licensed some of his technology. Where do similarities between worm and human end? Granted, the backbone of molecular pathways provided by C. elegans unites previous data on serotonin and metabolism under the umbrella of food signaling. Yet evolution has added flesh to this backbone as complex animals expanded their genomes and diversified their behavior. For example, worms eat constantly while humans eat intermittently, requiring more sophisticated regulation. Worms have no leptin, a hormone that controls eating. And the diversity of serotonin receptors in mammals far exceeds that in worms, accounting for the neurotransmitter's powerful role in mood control and its disorders and myriad other functions. �Gabrielle Strobel------------------ http://webpotential.com/ericibs/index.htm