The role of insulin signaling during development, reproductive diapause and aging in Drosophila Melanogaster

Sammanfattning: The insulin/insulin-like growth factor signaling pathway exists from invertebrates to vertebrates and it can regulate various biological processes, including development, metabolism, stress resistance and lifespan. In Drosophila, eight insulin-like peptides (DILP1-8) have been found. The specific function of each DILP is not fully known, especially for DILP1. In paper I, we found that dilp1 is specifically expressed in the brain insulin producing cells (IPCs), and it is mainly expressed from early pupa until few days of adult life, which correspond to non-feeding stages. The expression of dilp1 can last for at least 9 weeks of adult life when newborn virgin flies are induced to enter reproductive diapause. In addition, we found that the expression of dilp1 is under regulation by other dilps. Also larva-derived fat body, short neuropeptide F (sNPF) and juvenile hormone can affect dilp1 expression. We found that mutation of dilp1 affects female reproduction and starvation resistance. In paper II, we found that reproductive diapause can extend Drosophila life span, and at the same time ameliorate behavioral senescence, including negative geotaxis, activity rhythms and exploratory walking. Age-related changes in neuromuscular junction (NMJ) in abdominal muscle cannot be found in diapause-induced aging flies. The levels of several neuromodulators in the brain, including pigment dispersion factor (PDF), tyrosine hydroxylase (TH) and short neuropeptide F (sNPF), decreased significantly in normally aging flies, but less so in diapausing flies. In paper III, we show that mutation of dilp1 leads to a reduced organismal bodyweight, whereas overexpression increases it during the nonfeeding pupal stage. Overexpression of dilp1 additionally increases body size of flies, but reduces stores of larval-derived energy. This results in decreased starvation tolerance and increased feeding in newborn flies. In paper IV, we found that dilp1 expression is needed to extend lifespan in dilp2 mutant flies. Single dilp1 mutation has no effect on female lifespan, whereas transgene expression of dilp1 in flies with dilp1-dilp2 double mutant genetic background increased the lifespan. Furthermore, dilp1 and dilp2 interact to control circulating sugar, starvation resistance in a redundant or synergistic way.