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.

Keywords: insulin receptor; insulin release; insulin signaling; metabolism; neuromodulation; neuropeptide.

Figure 1

Insulin-producing cells (IPCs) in the Drosophila nervous system and gut. A set of 14 IPCs (blue) in pars intercerebralis of the brain send axons to the tritocerebrum (adjacent to the subesophageal ganglion, SEG), to the corpora cardiaca (CC) with associated aorta, proventriculus (PV), and the crop. Likely release sites for circulating Drosophila insulin-like peptides (DILPs) are in CC, aorta, PV, and crop. These IPCs produce DILP2, 3, and 5. The branches in protocerebrum (near cell bodies) and tritocerebrum of the brain could be dendritic and/or represent further release sites. A second set of 20 cells (aIPCs; red) is found in the abdominal neuromeres of the ventral nerve cord (VNC). These produce DILP7 and supply axon terminations to the hindgut including the rectal papillae (RP), and in females to reproductive organs (not shown here). At least two of the aIPCs send axons to the SEG. It is not clear whether their branches in the SEG are dendrites or release sites (or both). Additionally the principal cells (green) of the renal tubules (RT) produce DILP5. This DILP may act locally in the tubules. DILP6 is produced in fat body cells in the head and abdomen. The fat body also releases a leptin-like peptide, unpaired 2 (Upd2). Both DILP6 and Upd2 regulate IPC activity. In the midgut there are peptidergic endocrine cells (GEC) that may release peptides into the circulation to target cells in renal tubules and brain. This figure is updated and modified from Nässel (2012) which was partly based on Cognigni et al. (2011).

Figure 2

Insulin-producing cells (IPCs) and other neurons in the Drosophila brain. (A) The IPCs are seen with their cell bodies dorsally, two sets of presumed dendrites (Dendr 1 and 2) in the pars intercerebralis and processes branching in the (tritocerebrum Trito). It is not known whether these branches are dendrites or axon terminations, or both. The axons that exit to the corpora cardiaca and aorta are not displayed (they exit above the tritocerebrum, in a direction toward the reader). The antennal lobes (AL) are depicted with the anterior 10 (green and yellow) of the about 14 glomeruli that contain olfactory sensory neurons (OSNs) expressing short neuropeptide F (sNPF). The yellow glomeruli are DM1 that receive OSNs expressing odorant receptor Or42b and sNPF, known to be essential for food search. These sNPF-expressing OSNs also express the insulin receptor (dInR) and the sNPF receptor. DILPs are known to modulate odor sensitivity of these OSNs (Root et al., 2011). The mushroom bodies with calyx (Ca), α-, β- and γ-lobes (α L, β γ L) and the lateral horn (LH) are also depicted. The mushroom bodies also seem to be targeted by DILPs, at least in larvae (Zhao and Campos, 2012). (B) The IPCs (magenta, anti-DILP2) and corazonin-expressing DLP neurons (GFP, green) converge medially in the pars intercerebralis (encircled) and in the tritocerebrum (Trito). The DLPs are known to regulate IPC activity (Kapan et al., 2012). Arrows indicate the likely dendrites of the DLPs. (B1) Detail of IPCs (enhanced color) visualizing the short dendrites (Dendr 2) that seem to receive inputs from DLPs. (C) Schematic depiction of IPCs, DLPs and their point of convergence in the pars intercerebralis (Reg). The IPCs are located in the MNC cluster and the DLPs among the LNCs. For further details see Figure 3. (D) The IPCs (green) may receive inputs from serotonin-producing neuron branches (magenta) both at the long dendrites (Dendr 1) and the short (not shown here). Panel (B) is altered from Kapan et al. (2012) and 2D from Luo et al. (2012).

Figure 3

Sets of peptidergic neurons in the Drosophila brain that are associated with the IPCs. Some of the IPCs co-express drosulfakinins (DSK1 and 2), peptides that induce satiety (Söderberg et al., 2012). The IPCs are regulated by DLP neurons that produce short neuropeptide F (sNPF), corazonin (CRZ) and proctolin (Proct) (Isaac et al., ; Kapan et al., 2012) as well as GABAergic neurons (GSN) that in turn receive leptin-like (Upd2) signals from the fat body (Rajan and Perrimon, 2012). The GSNs express a Upd2-activated Jak/Stat receptor (Dome). The interactions between DLPs and GSNs and IPCs probably occur dorso-medially (IDR) in the pars intercerebralis and maybe in the tritocerebrum (TC). Another set of lateral neurosecretory cells (LNCs), designated ipc-1 and ipc-2a, express the peptides sNPF, Drosophila tachykinin (DTK) and ion transport peptide (ITP) (Kahsai et al., 2010). These neurons, like the DLPs, are parts of the LNC clusters and have axon terminations in sites overlapping those of the IPCs and the DLPs in the corpora cardiaca and anterior aorta. Further abbreviations: STAT, Jak/stat receptor Dome; MT, medially projecting axon tract; PLT, posterior lateral axon tract; MB, median bundle; NCC, nerves to corpora cardiaca. Asterisk indicates region where dendrites of DLPs arborize.

Figure 4

Summary of factors regulating brain IPCs. The brain IPCs are regulated by neurotransmitters (including neuropeptides) from neurons in the brain (red and green arrows) in a stimulatory (+) or inhibitory (−) fashion. These neurons are in turn likely to be activated by nutritional signals from the circulation, fat body or intestine. Some of these signals may act directly on the IPCs. UPD2 inactivates GABAergic neurons that then relieves tonic inhibition of IPCs (Rajan and Perrimon, 2012) and circulating fructose acts on brain neurons expressing the fructose receptor Gr43a (Miyamoto et al., 2012). Gut peptides include allatostatin A, DH31 and tachykinins (DTKs), known to have receptors on neurons regulating IPCs or directly on IPCs (Johnson et al., ; Veenstra, ; Birse et al., 2011). Circulating glucose has been proposed to be sensed by IPCs via uptake, entering glycolysis and the resulting ATP blocking ATP-sensitive K⁺ channels on IPCs leading to membrane depolarization and subsequent opening of voltage sensitive Ca²⁺ channels (Kreneisz et al., 2010). PV, proventriculus; SEG, subesophageal ganglion. Not shown here is the expression of an adiponectin-like receptor in IPCs (Kwak et al., 2013). This receptor may be targeted by a hitherto unidentified adipokine signal from the fat body.