A local insulin reservoir in Drosophila alpha cell homologs ensures developmental progression under nutrient shortage

Ghosh, Suhrid; Leng, Weihua; Wilsch‐Bräuninger, Michaela; Barrera-Velázquez, Mariana; Léopold, Pierre; Eaton, Suzanne

doi:10.1016/j.cub.2022.02.068

Cited by 9 publications

(6 citation statements)

References 54 publications

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“…While the functions of Drosophila ITPL1 are still unknown, the other neuropeptides have been shown to regulate osmotic and metabolic stress responses (Johnson et al ., 2005, Kahsai et al ., 2010, Zandawala et al ., 2018a, Diaz-de-la-Pena et al ., 2020). Interestingly, both L-NSC ITP and L-NSC DH31 also express ImpL2, an insulin-binding protein which enables cells to sequester insulin (Bader et al ., 2013, Galikova et al ., 2018, Ghosh et al ., 2022). These ITP neurons can thus act as a reservoir for insulin-like peptides and could release them along with other neuropeptides to modulate both osmotic and metabolic homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Anti-diuretic hormone ITP signals via a guanylate cyclase receptor to modulate systemic homeostasis inDrosophila

Gera,

Agard,

Nave

et al. 2024

Preprint

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Insects have evolved a variety of neurohormones that enable them to maintain their nutrient and osmotic homeostasis. While the identities and functions of various insect metabolic and diuretic hormones have been well-established, the characterization of an anti-diuretic signaling system that is conserved across most insects is still lacking. To address this, here we characterized the ion transport peptide (ITP) signaling system inDrosophila. TheDrosophila ITPgene encodes five transcript variants which generate three different peptide isoforms: ITP amidated (ITPa) and two ITP-like (ITPL1 and ITPL2) isoforms. Using a combination of anatomical mapping and single-cell transcriptome analyses, we comprehensively characterized the expression of all three ITP isoforms in the nervous system and peripheral tissues. Our analyses reveal widespread expression of ITP isoforms. Moreover, we show that ITPa is released during dehydration and recombinantDrosophilaITPa inhibits diuretic peptide-induced renal tubule secretionex vivo, thus confirming its role as an anti-diuretic hormone. Using a phylogenetic-driven approach and theex vivosecretion assay, we identified and functionally characterized Gyc76C, a membrane guanylate cyclase, as an elusiveDrosophilaITPa receptor. Thus, knockdown of Gyc76C in renal tubules abolishes the inhibitory effect of ITPa on diuretic hormone secretion. Extensive anatomical mapping of Gyc76C reveals that it is highly expressed in larval and adult tissues associated with osmoregulation (renal tubules and rectum) and metabolic homeostasis (fat body). Consistent with this expression, knockdown of Gyc76C in renal tubules impacts tolerance to osmotic and ionic stresses, whereas knockdown specifically in the fat body impacts feeding, nutrient homeostasis and associated behaviors. We also complement receptor knockdown experiments with ITPa overexpression in ITP neurons. Interestingly, ITPa-Gyc76C pathways deciphered here are reminiscent of the atrial natriuretic peptide signaling in mammals. Lastly, we utilized connectomics and single-cell transcriptomics to identify synaptic and paracrine pathways upstream and downstream of ITP-expressing neurons. Taken together, our systematic characterization of the ITP signaling establishes a tractable system to decipher how a small set of neurons integrates diverse inputs to orchestrate systemic homeostasis inDrosophila.

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Section: Discussionmentioning

confidence: 99%

Anti-diuretic hormone ITP signals via a guanylate cyclase receptor to modulate systemic homeostasis inDrosophila

Gera,

Agard,

Nave

et al. 2024

Preprint

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“…There is evidence of limited insulin production in some areas of the CNS [ 156 ]. Perhaps the limited CNS insulin production can have immediate effects in the local milieu, which has recently been shown in drosophila [ 157 ]. However, if these areas affect the larger picture of CNS insulin, much of what is currently believed would have to be reconsidered.…”

Section: Contributions Of the Periphery To Cns Insulin Actionsmentioning

confidence: 99%

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

2022

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The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.

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“…A very recent study has now shown that ImpL2 expressed by corpora-cardiaca (CC) helps "store" DILP2/5 to make them available under conditions of starvation that the animal in the late larval stage might encounter post the nutrient restricting checkpoint (NRC). Under these conditions, DILPS stored in the CC activate insulin signaling in the prothoracic gland to trigger ecdysone release essential for pupariation (Ghosh et al, 2022). The ImpL2 neurons thus serve as an example of neurons associated with restricting insulin signaling along the brainring gland axis.…”

Section: Neurons Insulin-like Peptides and Ecdysone Signalingmentioning

confidence: 99%

Neural pathways in nutrient sensing and insulin signaling

Ratnaparkhi

Sudhakaran

2022

Front. Physiol.

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Nutrient sensing and metabolic homeostasis play an important role in the proper growth and development of an organism, and also in the energy intensive process of reproduction. Signals in response to nutritional and metabolic status is received and integrated by the brain to ensure homeostasis. In Drosophila, the fat body is one of the key organs involved in energy and nutrient sensing, storage and utilization. It also relays the nutritional status of the animal to the brain, activating specific circuits which modulate the synthesis and release of insulin-like peptides to regulate metabolism. Here, we review the molecular and cellular mechanisms involved in nutrient sensing with an emphasis on the neural pathways that modulate this process and discuss some of the open questions that need to be addressed.

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A local insulin reservoir in Drosophila alpha cell homologs ensures developmental progression under nutrient shortage

Cited by 9 publications

References 54 publications

Anti-diuretic hormone ITP signals via a guanylate cyclase receptor to modulate systemic homeostasis inDrosophila

Anti-diuretic hormone ITP signals via a guanylate cyclase receptor to modulate systemic homeostasis inDrosophila

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites

Neural pathways in nutrient sensing and insulin signaling

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