The Proprotein Convertase Encoded by amontillado (amon) Is Required in Drosophila Corpora Cardiaca Endocrine Cells Producing the Glucose Regulatory Hormone AKH

Rhea, Jeanne M.; Wegener, Christian; Bender, Michael

doi:10.1371/journal.pgen.1000967

Cited by 41 publications

(55 citation statements)

References 64 publications

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“…Although Akh mRNA levels were not significantly different between ppk28 mutant and control flies (Fig. S4C), previous work in both the locust (Locusta migratoria) and Drosophila suggests that Akh gene transcription is uncoupled from neuropeptide release and that the neuropeptide may be discharged in a controlled fashion from a pool of continuously synthesized protein (36,37). To determine whether loss of ppk28 affected AKH release or sequestration, we directly imaged neuropeptide localization in dissected CC from adult flies stained with a dAKH-specific antibody (26).…”

Section: Ppk28-mediated Lifespan Extension Requires Components Of Nutmentioning

confidence: 64%

Water sensor ppk28 modulates Drosophila lifespan and physiology through AKH signaling

Waterson¹,

Chung

Harvanek

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Ppk28-mediated Lifespan Extension Requires Components Of Nutmentioning

confidence: 64%

Water sensor ppk28 modulates Drosophila lifespan and physiology through AKH signaling

Waterson¹,

Chung

Harvanek

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…While we cannot rule out the possibility that AMPK may be impacting AKH hormone processing, we consider this insufficient to explain the ensemble of phenotypes associated with reduced AMPK function in AKH cells. First, we observed partial phenocopies of AKH cell ablation, whereas in contrast, the loss of processing causes complete loss of function phenotypes (Rhea et al 2010). Second, our observation of delayed locomotor responses present in animals with compromised AMPK function suggests at least minimal levels of bioactive AKH as the complete loss of the hormone eliminates this behavioral response.…”

Section: Discussionmentioning

confidence: 75%

“…Processing of the AKH peptide relies on cleavage of the prohormone and subsequent amidation of the N terminus, and these events are required for AKH bioactivity (Rhea et al 2010). While we cannot rule out the possibility that AMPK may be impacting AKH hormone processing, we consider this insufficient to explain the ensemble of phenotypes associated with reduced AMPK function in AKH cells.…”

Section: Discussionmentioning

confidence: 99%

Energy-Dependent Modulation of Glucagon-Like Signaling inDrosophilavia the AMP-Activated Protein Kinase

Braco¹,

Gillespie²,

Alberto³

et al. 2012

Genetics

102

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Adipokinetic hormone (AKH) is the equivalent of mammalian glucagon, as it is the primary insect hormone that causes energy mobilization. In Drosophila, current knowledge of the mechanisms regulating AKH signaling is limited. Here, we report that AMP-activated protein kinase (AMPK) is critical for normal AKH secretion during periods of metabolic challenges. Reduction of AMPK in AKH cells causes a suite of behavioral and physiological phenotypes resembling AKH cell ablations. Specifically, reduced AMPK function increases life span during starvation and delays starvation-induced hyperactivity. Neither AKH cell survival nor gene expression is significantly impacted by reduced AMPK function. AKH immunolabeling was significantly higher in animals with reduced AMPK function; this result is paralleled by genetic inhibition of synaptic release, suggesting that AMPK promotes AKH secretion. We observed reduced secretion in AKH cells bearing AMPK mutations employing a specific secretion reporter, confirming that AMPK functions in AKH secretion. Live-cell imaging of wild-type AKH neuroendocrine cells shows heightened excitability under reduced sugar levels, and this response was delayed and reduced in AMPK-deficient backgrounds. Furthermore, AMPK activation in AKH cells increases intracellular calcium levels in constant high sugar levels, suggesting that the underlying mechanism of AMPK action is modification of ionic currents. These results demonstrate that AMPK signaling is a critical feature that regulates AKH secretion, and, ultimately, metabolic homeostasis. The significance of these findings is that AMPK is important in the regulation of glucagon signaling, suggesting that the organization of metabolic networks is highly conserved and that AMPK plays a prominent role in these networks.

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“…Neuropeptides that are released from neurosecretory cells typically require processing of precursor forms by the proprotein convertase encoded by amontillado (amon) 57 . Following processing, mature peptides are packaged into dense core vesicles, which require the function of Caps (calcium-activated protein for secretion) for subsequent release of these vesicles 58 .…”

Section: Resultsmentioning

confidence: 99%

Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis

et al. 2014

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Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour.

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The Proprotein Convertase Encoded by amontillado (amon) Is Required in Drosophila Corpora Cardiaca Endocrine Cells Producing the Glucose Regulatory Hormone AKH

Cited by 41 publications

References 64 publications

Water sensor ppk28 modulates Drosophila lifespan and physiology through AKH signaling

Water sensor ppk28 modulates Drosophila lifespan and physiology through AKH signaling

Energy-Dependent Modulation of Glucagon-Like Signaling inDrosophilavia the AMP-Activated Protein Kinase

Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis

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