Big Mac and Flies: Signaling pathway tells insects when food's on the table (Insulin-related signaling)

Abstract

Like a dinner bell, an insulin-related signaling pathway tells fruit fly larvae when food is plentiful, according to new work. The results suggest that the insects could be used to study diabetes and other metabolic disorders. In addition, they support a theory to explain how caloric restriction extends life-span in mammals. In humans and other furry creatures, insulin alerts cells when sugar has hit the bloodstream--after a big meal, for instance. Nematodes and fruit flies carry signaling systems whose components resemble those in the mammalian insulin pathway. These systems influence cell growth and life-span. Mutations in members of the worm and fly pathways can dramatically increase longevity (see "Growing Old Together" and Genes/Interventions Database entries daf-2 , InR , and chico ). But whether food sends signals flying in flies as it does in mammals has been unclear. Britton and colleagues found the answer to that question while investigating the early development of Drosophila . The researchers soaked up a key component of the pathway--an enzyme called PI3 kinase (PI3K)--by engineering larvae to produce large amounts of a PI3K-binding protein. The larvae with quashed PI3K--and hence reduced insulin-related signaling--mimicked starved flies: They stopped growing and delayed maturation for as long as 2 weeks. The group wondered whether the insulin-related pathway might be responsible for sensing nutrients. To test this idea, the team engineered fly larvae to produce an easily detectable marker of insulin-related signaling. When the pathway flips on, this fluorescent protein migrates from the inside of a cell to its membrane. By tracking the location of the marker protein, the researchers could determine whether the insulin-related pathway had been activated. When the engineered larvae were starved, the protein did not color cell membranes. By contrast, when food was abundant, it painted a ring around cells. This difference suggests that insulin-related signaling alerts cells to the presence of sustenance. Further studies indicate that the survival of a larva depends on the ability of the insulin-related system to monitor nutrient amounts. The team cranked up pathway activity by engineering a few cells in a larva to produce copious amounts of a key component. Those cells continued to grow and stockpile nutrients even when starved, whereas their normal neighbors did not. Ramping up the insulin-related signaling pathway in many cells had dire consequences, however. With a paucity of food, the engineered larvae survived only half as long as normal bugs did. With too many cells trying to grow in the absence of nourishment, the creatures were probably cannibalizing themselves, say experts. Together, the results suggest that when provisions are plentiful--or when the insects are tricked into thinking that they are--the activated insulin-related pathway tells flies to grow and continue their progress toward adulthood. A lack of chow turns off signaling, and flies hunker down to wait until conditions improve. If adult flies also use the insulin-related pathway to sense the presence of food, the insects could provide a new model for human metabolic diseases such as diabetes. In addition, the findings bolster the notion that caloric restriction--the only known treatment to extend life-span in mammals--increases longevity at least in part by altering insulin-related signaling. Dieting rodents display a range of hormonal changes, including unusually small amounts of insulin. The dinner bell makes mouths water, but dampening its ring might harbinger a longer time for satisfaction. --R. John Davenport; suggested by Yuji Ikeno and Arlan Richardson J. S. Britton, W. K. Lockwood, L. Li, S. M. Cohen, B. A. Edgar, Drosophila 's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev. Cell 2 , 239-249 (2002). [Abstract] [Full Text]