Eat to reproduce: a key role for the insulin signaling pathway in adult insects

Abstract

Insects, like all heterotrophic organisms, acquire from their food the nutrients that are essential for anabolic processes that lead to growth (larval stages) or reproduction (adult stage). In adult females, this nutritional input is processed and results in a very specific output, i.e., the production of fully developed eggs ready for fertilization and deposition. An important role in this input-output transition is attributed to the insulin signaling pathway (ISP). The ISP is considered to act as a sensor of the organism's nutritional status and to stimulate the progression of anabolic events when the status is positive. In several insect species belonging to different orders, the ISP has been demonstrated to positively control vitellogenesis and oocyte growth. Whether or not ISP acts herein via a mediator action of lipophilic insect hormones (ecdysteroids and juvenile hormone) remains debatable and might be differently controlled in different insect orders. Most likely, insulin-related peptides, ecdysteroids and juvenile hormone are involved in a complex regulatory network, in which they mutually influence each other and in which the insect's nutritional status is a crucial determinant of the network's output. The current review will present an overview of the regulatory role of the ISP in female insect reproduction and its interaction with other pathways involving nutrients, lipophilic hormones and neuropeptides.

Keywords: female insect reproduction; insulin signaling pathway; lipophilic hormones; neuropeptides; nutritional status.

Figure 1

Simplified schematic representation of the insulin and TOR signaling pathways as they have been described in mammals and for which orthologous components have been described in D. melanogaster and some other insects. For a detailed overview of the pathway components the reader is referred to the text. Dashed lines represent indirect interactions. Abbreviations: ILP, insulin-like peptide; IR, insulin receptor; IRS, insulin receptor substrate; Grb2, growth factor receptor bound protein-2 [the Drosophila ortholog of which is termed the “downstream of receptor kinase” (Drk)]; Sos, son of sevenless; MEK, mitogen-activated ERK-activating kinase; ERK, extracellular signal regulated kinase; PI3K, phosphatidylinositol-3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin homologue; PDK, phosphoinositide-dependent protein kinase; FOXO, forkhead box-related transcription factors, class O; TSC1-2, tuberous sclerosis 1-2 complex; TOR, target of rapamycin. [Figure adapted from Claeys et al. (2002).]

Figure 2

Schematic overview of the key players in ISP-mediated control of female insect reproductive physiology. Solid lines represent a consensus, a process that has been demonstrated in several insect orders. [It needs to be emphasized that the role of ISP in honeybee reproduction strongly deviates from the consensus. Therefore, information from the honeybee is not taken into account in this overview.] Dashed lines represent processes that have only been demonstrated in a limited number of insect species or orders, or that may possibly act more indirectly than suggested on the figure. These lines go accompanied by a remark, indicated by a superscript character. Nutrient-related (signaling) pathways (red arrows): Upon digestion of food in the midgut, nutrients are absorbed by the midgut cells and subsequently released into the hemolymph. They are either directly used by the tissues as a source of metabolic energy or as a substrate in anabolic reactions, or they are stored in fat body cells. The fat body's nutritional stores may then be mobilized for the production of vitellogenins, energetic substrates and other metabolic products that serve the process of oogenesis within the ovary. The TOR signaling pathway constitutes a conserved cellular nutrient (amino acid)-sensing system (Hietakangas and Cohen, 2009) and is therefore indispensable in the control of vitellogenin synthesis in the fat body. ^(a) Glucose availability stimulates the in vivo release of bombyxin from the silkworm brain, although a direct effect on the brain has so far not been proven (Masumura et al., 2000). Although the isolated fruit fly brain does not seem to release ILPs in response to glucose in vitro (Geminard et al., 2009), it is worth noting that some electrical properties of ILP producing brain cells appear to be affected by the glucose (Fridell et al., ; Kreneisz et al., 2010). ^(b) A hitherto unknown humoral factor that stimulates ILP release from the fruit fly brain is released from the fat body via a TOR-mediated response to the presence of amino acids (Colombani et al., ; Geminard et al., 2009). ^(c) Similarly, the cytokine-like factor Unpaired 2 is produced in the fat body in response to dietary fats and sugar. Remarkably, Unpaired 2 also appears to induce the release of ILP from the fruit fly brain. Although Unpaired 2 has so far not been demonstrated in the fruit fly hemolymph circulation in vivo, the authors of the corresponding report suggested that this protein may act as a humoral factor (Rajan and Perrimon, 2012). Lipophilic hormone signaling (green arrows): Ecdysteroids are in adult insects mainly synthesized by the gonads. In females they fulfill auto- and paracrine roles in ovary and oocyte development. In addition, ecdysteroid conjugates are stored in the eggs as an embryonic source of these lipophilic hormones. Juvenile hormone is produced by the CA. It stimulates vitellogenin production by the fat body, as well as vitellogenin sequestration by the developing oocytes. ^(d) In dipteran species, an endocrine function for the ecdysteroids in the regulation of vitellogenin synthesis has been demonstrated (Huybrechts and De Loof, 1977). An endocrine role seems to be attributed to ecdysteroids in B. mori too, since in this insect they are capable of stimulating ILP synthesis in the fat body (Okamoto et al., 2009, 2011). Remarkably, the decline of ecdysteroids appears to be crucial for termination of vitellogenesis in both A. aegypti and B. mori, indicating that the outcome of ecdysteroid action in reproductive physiology is stage-dependent and species-specific (Dhadialla et al., ; Swevers and Iatrou, ; Bryant and Raikhel, 2011). ^(e) In the beetle T. castaneum a stimulatory effect of JH on expression of some ILP genes in brain and fat body was shown (Sheng et al., 2011). ILP signaling (blue arrows): A stimulatory role of insulin signaling on JH biosynthesis has been shown in several insect orders, ^(f) although it is not clear whether ILPs are directly delivered to the CA by projections of the CC or whether they are received from the circulating hemolymph (Tu et al., ; Belgacem and Martin, 2006). ^(g) A stimulatory effect of ILPs on ovarian ecdysteroidogenesis has so far only been demonstrated in dipteran species (Tu et al., ; Brown et al., ; Wen et al., 2010). ^(h) Direct ILP-mediated positive control of oogenesis has hitherto only been shown in D. melanogaster (Drummond-Barbosa and Spradling, ; LaFever and Drummond-Barbosa, ; Richard et al., 2005) and T. castaneum (Parthasarathy and Palli, 2011). ⁽ⁱ⁾ Similarly, direct ILP-mediated stimulation of vitellogenesis has so far only been observed in Diptera (Roy et al., ; Gulia-Nuss et al., 2011) and in T. castaneum (Parthasarathy and Palli, ; Sheng et al., 2011). ^(j) In some insect species, ILP synthesis also occurs in the fat body (Badisco et al., ; Okamoto et al., 2009). In the desert locust, S. gregaria, the expression levels in this tissue are temporally regulated during the reproductive cycle (Badisco et al., 2008). It is therefore possible that ILP produced by the fat body also acts, at least in this insect species, as a paracrine messenger that signals information about the nutritional status within this tissue and stimulates vitellogenin production (Badisco et al., 2011). Abbreviations: CA, corpora allata; CC, corpora cardiaca; ILP, insulin-like peptide; JH, juvenile hormone; TOR, target of rapamycin.