Factors that regulate insulin producing cells and their output in Drosophila

Abstract

Insulin-like peptides (ILPs) and growth factors (IGFs) not only regulate development, growth, reproduction, metabolism, stress resistance, and lifespan, but also certain behaviors and cognitive functions. ILPs, IGFs, their tyrosine kinase receptors and downstream signaling components have been largely conserved over animal evolution. Eight ILPs have been identified in Drosophila (DILP1-8) and they display cell and stage-specific expression patterns. Only one insulin receptor, dInR, is known in Drosophila and most other invertebrates. Nevertheless, the different DILPs are independently regulated transcriptionally and appear to have distinct functions, although some functional redundancy has been revealed. This review summarizes what is known about regulation of production and release of DILPs in Drosophila with focus on insulin signaling in the daily life of the fly. Under what conditions are DILP-producing cells (IPCs) activated and which factors have been identified in control of IPC activity in larvae and adult flies? The brain IPCs that produce DILP2, 3 and 5 are indirectly targeted by DILP6 and a leptin-like factor from the fat body, as well as directly by a few neurotransmitters and neuropeptides. Serotonin, octopamine, GABA, short neuropeptide F (sNPF), corazonin and tachykinin-related peptide have been identified in Drosophila as regulators of IPCs. The GABAergic cells that inhibit IPCs and DILP release are in turn targeted by a leptin-like peptide (unpaired 2) from the fat body, and the IPC-stimulating corazonin/sNPF neurons may be targeted by gut-derived peptides. We also discuss physiological conditions under which IPC activity may be regulated, including nutritional states, stress and diapause induction.

Circadian and feeding cues integrate to drive rhythms of physiology in Drosophila insulin-producing cells

“…This manipulation caused a moderate loss of sxe2 rhythm, but, as reaper ablation of IPCs is associated with other deleterious phenotypes (Rulifson et al 2002), we examined insulin-like peptide (ILP) signaling directly. The IPCs produce three ILPs-ILP2, ILP3, and ILP5-of which ILP2 is most analogous to mammalian insulin (Nässel et al 2013). To determine whether the effect on sxe2 cycling was due to loss of any of these peptides, we examined mutants lacking ILP2 as well as those lacking ILP2, ILP3, and ILP5 together.…”

“…However, the mechanisms underlying rhythmic insulin secretion are not known. Although less complex and not yet implicated in metabolic rhythms, the Drosophila insulin signaling pathway is similar to that in mammals and is important for metabolism (Rulifson et al 2002;Haselton and Fridell 2010;Nässel et al 2013). A major target of insulin in flies is the fat body, a tissue analogous to mammalian liver and adipose tissue with roles in feeding behavior and metabolism (Xu et al 2008;Arrese and Soulages 2010).…”

The neurobiology of the Prader-Willi phenotype of fragile X syndrome

“…Metabolic anomalies including increased glucose uptake and excess protein synthesis in the brain have been reported in Fmr1 KO mice, while in the fly (dfmr1), it has been shown that FMRP is required during brain development and may function in neuroblast reactivation by regulating an output of the insulin signaling pathway (48)(49)(50)(51)(52). Metabolic profiling in the Fmr1 KO mice also revealed profound consequences in brain metabolism, which in turn lead to alterations in the metabolic response, along with anomalies in other physiological processes and behaviors (53).…”

Longevity and stress resistance are affected by activation of TOR/Myc in progenitor cells of Drosophila gut

“…This fly phenotype closely resembles the aging phenotype. Treatment with stressful agents, such as paraquat exposure which induces oxidative stress, has been shown to increase ISC number and activity in the guts Drosophila [43,44]. Additionally, Okamoto and Nishmura [43] illustrated the existence of a feedback mechanism between DILPs and FOXO.…”