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Insulin Signaling, Lifespan and Stress Resistance Are Modulated by Metabotropic GABA Receptors on Insulin Producing Cells in the Brain of Drosophila
Stockholm University, Faculty of Science, Department of Zoology.
Stockholm University, Faculty of Science, Department of Zoology, Functional Morphology.
Stockholm University, Faculty of Science, Department of Zoology, Functional Morphology.
Stockholm University, Faculty of Science, Department of Zoology, Functional Morphology.
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2010 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 12, e15780- p.Article in journal (Refereed) Published
Abstract [en]

Insulin-like peptides (ILPs) regulate growth, reproduction, metabolic homeostasis, life span and stress resistance in worms, flies and mammals. A set of insulin producing cells (IPCs) in the Drosophila brain that express three ILPs (DILP2, 3 and 5) have been the main focus of interest in hormonal DILP signaling. Little is, however, known about factors that regulate DILP production and release by these IPCs. Here we show that the IPCs express the metabotropic GABA(B) receptor (GBR), but not the ionotropic GABA(A) receptor subunit RDL. Diminishing the GBR expression on these cells by targeted RNA interference abbreviates life span, decreases metabolic stress resistance and alters carbohydrate and lipid metabolism at stress, but not growth in Drosophila. A direct effect of diminishing GBR on IPCs is an increase in DILP immunofluorescence in these cells, an effect that is accentuated at starvation. Knockdown of irk3, possibly part of a G protein-activated inwardly rectifying K(+) channel that may link to GBRs, phenocopies GBR knockdown in starvation experiments. Our experiments suggest that the GBR is involved in inhibitory control of DILP production and release in adult flies at metabolic stress and that this receptor mediates a GABA signal from brain interneurons that may convey nutritional signals. This is the first demonstration of a neurotransmitter that inhibits insulin signaling in its regulation of metabolism, stress and life span in an invertebrate brain.

Place, publisher, year, edition, pages
2010. Vol. 5, no 12, e15780- p.
National Category
Biological Sciences
Research subject
Functional Zoomorphology
Identifiers
URN: urn:nbn:se:su:diva-53298DOI: 10.1371/journal.pone.0015780ISI: 000285793600039PubMedID: 21209905OAI: oai:DiVA.org:su-53298DiVA: diva2:390391
Available from: 2011-01-21 Created: 2011-01-21 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Chemical signalling in the Drosophila brain: GABA, short neuropeptide F and their receptors
Open this publication in new window or tab >>Chemical signalling in the Drosophila brain: GABA, short neuropeptide F and their receptors
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gamma-aminobutyric acid (GABA) and short neuropeptide F (sNPF) are widespread signalling molecules in the brain of insects. In order to understand more about the signalling and to some extent start to unravel the functional roles of these two substances, this study has examined the locations of the transmitters and their receptors in the brain of the fruit fly Drosophila melanogaster using immunocytochemistry in combination with Gal4/UAS technique. The main focus is GABA and sNPF in feeding circuits and in the olfactory system. We found both GABA receptor types in neurons in many important areas of the Drosophila brain including the antennal lobe, mushroom body and the central body complex. The metabotropic GABAB receptor (GABABR) is expressed in a pattern similar to the ionotropic GABAAR, but some distribution differences can be distinguished (paper I). The insulin producing cells contain only GABABR, whereas the GABAAR is localized on neighbouring neurons. We found that GABA regulates the production and release of insulin-like peptides via GABABRs (paper II). The roles of sNPFs in feeding and growth have previously been established, but the mechanisms behind this are unclear. We mapped the distribution of sNPF with antisera to the sNPF precursor and found the peptide in a large variety of interneurons, including the Kenyon cells of the mushroom bodies, as well as in olfactory sensory neurons that send axons to the antennal lobe (paper III). We also mapped the distribution of the sNPF receptor in larval tissues and found localization in six median neurosecretory cells that are not insulin-producing cells, in neuronal branches in the larval antennal lobe and in processes innervating the mushroom bodies (paper IV).

In summary, we have studied two different signal substances in the Drosophila brain (GABA and sNPF) in some detail. We found that these substances and their receptors are widespread, that both sNPF and GABA act in very diverse systems and that they presumably play roles in feeding, metabolism and olfaction.

Place, publisher, year, edition, pages
Stockholm: Department of Zoology, Stockholm University, 2011. 40 p.
Keyword
Insect nervous system, Drosophila, GABA, sNPF, GPCR, ion channel receptor, feeding, metabolic stress, olfaction, antennal, lobe, mushroom body
National Category
Zoology
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-56476 (URN)978-91-7447-291-2 (ISBN)
Public defence
2011-05-27, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.Available from: 2011-05-05 Created: 2011-04-18 Last updated: 2014-10-28Bibliographically approved
2. Neuropeptides and GABA in control of insulin producing cells in Drosophila
Open this publication in new window or tab >>Neuropeptides and GABA in control of insulin producing cells in Drosophila
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Insulin plays an important role in metabolic regulation as well as in growth, fecundity and stress resistance. In order to understand more about the regulation of insulin-like peptide (DILP) production and release we investigate the impact of neuropeptide (DTK) signaling and classical neurotransmitter (GABA) signaling onto the insulin producing cells of the Drosophila brain.

DTK was shown to regulate insulin production through DTK receptors found on the insulin producing cells of the brain. DTK has an impact on carbohydrate and lipid levels as well as effect stress resistance (Paper I). Manipulations of DTK signaling differentially affect Dilp transcript levels. We also showed that GABA regulates the production and release of insulin-like peptides via GABABRs (Paper II). Both these two signaling pathways have an inhibitory action on insulin production and release.

The Malpighian (renal) tubules were discovered as a novel site of insulin-like peptide expression and DTK signaling was shown to converge on the insulin pathway also here (Paper III). Stress seems to induce hormonal release of DTK that acts on the renal tubules to regulate DILP 5 signaling. Manipulations of superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP 5 acts locally on tubules, possibly in oxidative stress regulation.

Finally, we demonstrated that a cholecystokinin-like (CCK) peptide, DSK, is present in the IPCs and affects meal size regulation and food preference (Paper IV). DSK, like CCK, therefore acts to induce satiety. DSK and Dilp transcripts levels were also found to affect each other, suggesting coordination and possibly a feedback mechanism between the two signaling pathways.

In summary, we have studied control of Insulin signaling in Drosophila and have found that the different DILP isoforms have may separate functions and that they are separately regulated by both neuropeptides and classical neurotransmitters.

Place, publisher, year, edition, pages
Stockholm: Department of Zoology, Stockholm University, 2011. 40 p.
Keyword
Drosophila, insulin signaling, metabolism, feeding, DTK, DSK, GABA, stress resistance
National Category
Biological Sciences
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-62542 (URN)978-91-7447-374-2 (ISBN)
Public defence
2011-10-28, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 621-2007-6500
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript. Available from: 2011-10-06 Created: 2011-09-22 Last updated: 2012-01-12Bibliographically approved
3. Regulation of insulin producing cells, stress responses and metabolism in Drosophila
Open this publication in new window or tab >>Regulation of insulin producing cells, stress responses and metabolism in Drosophila
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Drosophila, neuropeptides have regulatory roles in development, growth, metabolism and reproduction. This study focused on GABA and the neuropeptides Drosophila tachykinin (DTK), short neuropeptide F (sNPF), adipokinetic hormone (AKH), corazonin (CRZ) and Drosophila insulin-like peptides (DILPs) as possible regulators of metabolic stress responses and homeostasis. We showed that metabotropic GABAB receptors (GBRs) are expressed on brain insulin producing cells (IPCs), suggesting an inhibitory regulation of these cells by GABA. Knockdown of GBR on IPCs shortened lifespan and stress resistance, altered carbohydrate and lipid metabolism at stress (paper I). We showed that three different neuropeptides; DTK, sNPF and ITP, are co-expressed in five pairs of adult neurosecretory cells (paper II). ITP-knock down was not studied yet, but sNPF- and DTK-knock down flies showed decreased stress resistance at desiccation and starvation and decreased water levels at desiccation, suggesting that these peptides are involved in water homeostasis during stress conditions. sNPF was previously shown to affect feeding, growth and DILP expression via the IPCs, but it was not known which sNPF-expressing neurons are responsible for these actions. We could identify a specific set of bilateral neurons (DLPs) that co-express sNPF and corazonin that target the IPCs. We showed that these peptides co-released from DLPs regulate DILP transcription and probably release in the adult Drosophila brain and thus have roles in regulation of stress resistance and metabolism (paper III). AKH signaling was previously shown to affect hemolymph carbohydrate levels and lipid stores in Drosophila. Insulin (DILP) signaling and AKH signaling are suggested to have opposing effects on lipid and sugar metabolism in Drosophila. We studied the possible functional relationship between these two systems; do they mutually regulate each other?  Our results suggest action of DILPs via the Insulin Receptor on the IPCs and the AKH producing cells, but we could not provide evidence for AKH action on IPCs or AKH cells (paper IV). 

Place, publisher, year, edition, pages
Stockholm, Sweden: Department of Zoology, Stockholm Univeristy, 2012. 33 p.
Keyword
Insulin signaling, Drosophila melanogaster, peptide hormones, neuropeptides, GABA
National Category
Cell Biology
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-80518 (URN)978-91-7447-582-1 (ISBN)
Public defence
2012-10-26, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Epub ahead of print. Paper 4: Manuscript.

Available from: 2012-10-04 Created: 2012-09-24 Last updated: 2014-10-28Bibliographically approved
4. Peptide and GABA regulation of Peptide Hormone Release in the Drosophila Brain
Open this publication in new window or tab >>Peptide and GABA regulation of Peptide Hormone Release in the Drosophila Brain
2010 (English)Licentiate thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Department of Zoology, Stockholm University, 2010. 39 p.
Series
Licentiatavhandling / Zoologiska institutionen, Stockholms universitet, ISSN 1403-5227
National Category
Zoology
Identifiers
urn:nbn:se:su:diva-65831 (URN)
Presentation
2010-12-07, 14:00 (English)
Opponent
Supervisors
Available from: 2013-01-25 Created: 2011-12-14 Last updated: 2014-10-28Bibliographically approved

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