Water sensor ppk28 modulates Drosophila lifespan and physiology through AKH signaling

Abstract

Sensory perception modulates lifespan across taxa, presumably due to alterations in physiological homeostasis after central nervous system integration. The coordinating circuitry of this control, however, remains unknown. Here, we used the Drosophila melanogaster gustatory system to dissect one component of sensory regulation of aging. We found that loss of the critical water sensor, pickpocket 28 (ppk28), altered metabolic homeostasis to promote internal lipid and water stores and extended healthy lifespan. Additionally, loss of ppk28 increased neuronal glucagon-like adipokinetic hormone (AKH) signaling, and the AKH receptor was necessary for ppk28 mutant effects. Furthermore, activation of AKH-producing cells alone was sufficient to enhance longevity, suggesting that a perceived lack of water availability triggers a metabolic shift that promotes the production of metabolic water and increases lifespan via AKH signaling. This work provides an example of how discrete gustatory signals recruit nutrient-dependent endocrine systems to coordinate metabolic homeostasis, thereby influencing long-term health and aging.taste | adipokinetic hormone signaling S ensory signaling systems are potent modulators of organismal metabolism and lifespan (1-6) but the mechanisms by which sensory inputs are transduced into relevant physiological outputs remain poorly understood. For even the simplest organisms, an extensive array of sensory stimuli-including chemical, mechanical, thermal, and visual cues-must be properly transduced and integrated to ensure a reliable response to environmental quality. In the nematode Caenorhabditis elegans, sensory neurons alone may accomplish these tasks. They express multiple sensory receptors, which provide simple integrative capabilities to the cell, and they secrete neuropeptides, which can direct cell-nonautonomous responses in peripheral tissues (7). The fruit fly, Drosophila melanogaster, however, is similar to mammals in that sensory neurons are often highly specialized, and elaborate mechanisms of sensory integration and interpretation are performed by specialized processing centers in the central brain (8). Once decoded, sensory signals are presumably relayed to neuroendocrine centers to stimulate appropriate actions in peripheral tissues. Whereas the release of endocrine molecules, including insulinlike peptides, via central nervous system (CNS) control has emerged as a critical regulator of aging across model organisms, the extent to which sensory signals impact such systems, and the underlying neurocircuitry involved, are unknown (9-11).The Drosophila system is a powerful tool for elucidating evolutionarily conserved aspects of neural circuitry that link sensory information to a variety of behavioral and metabolic responses. Although comprised of only ∼100,000 neurons, the fly brain is sufficiently complex to share many aspects of structure and function with humans and mice. This, along with the ability to manipulate neuronal activity in a temporally and spatially controlled manner, ha...

Positive and negative gustatory inputs affect Drosophila lifespan partly in parallel to dFOXO signaling

“…Interestingly, mutations that disrupt the Gr5a locus have previously been shown to decrease lifespan (46), consistent with our observation with a mutation that specifically deletes this gene [ΔGr5a (43); Table 1]. Moreover, the companion article (44) in PNAS details the mechanisms through which the water receptor ppk28 affects lifespan. Thus, our data together suggest the nature of some taste inputs that can modulate Drosophila longevity.…”

“…However, yeast restriction alone does not always increase fly lifespan under all conditions that do not cause malnutrition (52), which suggests that other lifespaninfluencing food-derived factors are also involved. In fact, the perception of water is one of the cues, among many, that can affect lifespan (Table 1) (44,54). Thus, because the gustatory system senses many different types of food-derived cues, which We measured the lifespan of control (ctrl) and mutant (mut) flies in parallel in independent trials.…”

“…The lifespan of some of the taste receptor mutants were measured as described in ref. 44, where flies were fed a 10% (wt/vol) sucrose and yeast diet (SY10) or a 30% (wt/vol) sucrose-5% (wt/vol) yeast diet (S30Y5).…”

Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

“…Consistently, AKH was identified as the hyperglycemic hormone in cockroaches (Steele 1961), as the hyperlipaemic hormone in Locusta (Beenakkers 1969;Mayer and Candy 1969) and as the hyperprolinaemic hormone in the fruit beetle Pachnoda sinuata (Auerswald and Gäde 1999). Next to this primary, catabolic role, numerous studies have implicated AKH in a puzzling diversity of additional physiological functions ranging from behavior (Kaun et al 2008), locomotion (Kodrík et al 2000;Socha et al 2008), and reproduction (Lorenz 2003;Attardo et al 2012) to digestion (Vinokurov et al 2014), heart beat control (Noyes et al 1995), sleep (Metaxakis et al 2014), immunity (Adamo et al 2008), oxidative stress resistance (Bednářová et al 2013a,b;Plavšin et al 2015), aging (Katewa et al 2012;Waterson et al 2014), and muscle contraction (Stoffolano et al 2014). It is not clear so far whether these pleiotropic effects of AKH result from changes in energy homeostasis, or rather reveal the existence of distinct AKH-regulated signaling pathways, which implement independent functions of AKH.…”

“…However, in contrast to the numerous scientific reports dealing with AKH roles in nondrosophilid species, only a limited number of studies have focused on AKH signaling in Drosophila so far. In the absence of a specific mutant, tools for AKH studies have remained limited to the ablations of CC cells (Kim and Rulifson 2004;Lee and Park 2004;Isabel et al 2005), stimulation of secretory activity of CC cells by their depolarization (Kim and Rulifson 2004), mutations of the receptor (Grönke et al 2007;Bharucha et al 2008;Waterson et al 2014), overexpression of Akh complementary DNA (cDNA) (Kim and Rulifson 2004;Lee and Park 2004;Grönke et al 2007;Katewa et al 2012;Baumbach et al 2014b), and Akh RNA interference (RNAi) (Braco et al 2012;Baumbach et al 2014b). Ablation of CC cells, or their depolarization, are not AKH-specific manipulations, as these endocrine cells also produce other hormones like limostatin, which affects metabolism by regulation of insulin signaling (Alfa et al 2015).…”