Nutritional control of body size through FoxO-Ultraspiracle mediated ecdysone biosynthesis

The development of many of an animal's traits and characteristics are sensitive to the conditions of its environment. The conditions experienced early on in life, in particular, can alter how an animal grows and develops. The availability of food during development, for example, affects the final body size of many animals—including the larvae of fruit flies, which must reach a so-called ‘critical weight’ before they can change into adults. A hormone called ecdysone controls when a larva turns into an adult insect. This hormone's levels peak when a fruit fly larva has reached its critical weight, and this peak triggers a cascade of events that ultimately will cause the larva to stop growing and to change into an adult fly. A signaling pathway involving insulin is also known to help regulate body size in response to nutrition. But it was unclear how the timing, and size, of the ecdysone peak is altered to match the larva's diet—and how the insulin-related pathway exerts its effect on body size. Now, Koyama et al. have found a molecular link between this signaling pathway and the ecdysone hormone that can explain how nutrition can regulate the growth of the flies. First, Koyama et al. found that the ecdysone peak is delayed when young fruit fly larvae were starved before they had reached the critical weight. On the other hand, feeding these starved larvae the ecdysone hormone prevented this delay; and many of these larvae developed into underweight adults that were about three-quarters the size of a typical fully-grown adult. The ecdysone hormone is made by cells within certain glands in the larvae. Koyama et al. also found that a protein called FoxO, which inhibits the insulin-related pathway, is transported out of the nuclei of these gland cells when growing larvae gain weight. But when larvae that had not reached their critical weight were starved, the FoxO protein was kept within the cell nuclei. Koyama et al. found that, in the nucleus, the FoxO protein blocks the production of ecdysone by interacting with a protein that forms part of the ecdysone receptor. This protein complex delays the expression of genes that are involved in making the hormone. When larvae were fed, the FoxO protein began to leave the nucleus, which allowed ecdysone production to resume. Future studies could now test whether FoxO controls other traits that are affected by the insect's diet (such as lifespan), and if growth-related hormones in other animals are affected by a similar mechanism.