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Neuropeptides and GABA in control of insulin producing cells in Drosophila
Stockholm University, Faculty of Science, Department of Zoology.
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 [en]
Drosophila, insulin signaling, metabolism, feeding, DTK, DSK, GABA, stress resistance
National Category
Biological Sciences
Research subject
Functional Zoomorphology
Identifiers
URN: urn:nbn:se:su:diva-62542ISBN: 978-91-7447-374-2 (print)OAI: oai:DiVA.org:su-62542DiVA: diva2:444432
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
List of papers
1. Insulin Production and Signaling in Renal Tubules of Drosophila is under Control of Tachykinin-related Peptide and Regulates Stress Resistance
Open this publication in new window or tab >>Insulin Production and Signaling in Renal Tubules of Drosophila is under Control of Tachykinin-related Peptide and Regulates Stress Resistance
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 5, e19866- p.Article in journal (Refereed) Published
Abstract [en]

The insulin-signaling pathway is evolutionarily conserved in animals and regulates growth, reproduction, metabolichomeostasis, stress resistance and life span. In Drosophila seven insulin-like peptides (DILP1-7) are known, some of whichare produced in the brain, others in fat body or intestine. Here we show that DILP5 is expressed in principal cells of the renaltubules of Drosophila and affects survival at stress. Renal (Malpighian) tubules regulate water and ion homeostasis, but alsoplay roles in immune responses and oxidative stress. We investigated the control of DILP5 signaling in the renal tubules byDrosophila tachykinin peptide (DTK) and its receptor DTKR during desiccative, nutritional and oxidative stress. The DILP5levels in principal cells of the tubules are affected by stress and manipulations of DTKR expression in the same cells.Targeted knockdown of DTKR, DILP5 and the insulin receptor dInR in principal cells or mutation of Dilp5 resulted inincreased survival at either stress, whereas over-expression of these components produced the opposite phenotype. Thus,stress seems to induce hormonal release of DTK that acts on the renal tubules to regulate DILP5 signaling. Manipulations ofS6 kinase and superoxide dismutase (SOD2) in principal cells also affect survival at stress, suggesting that DILP5 acts locallyon tubules, possibly in oxidative stress regulation. Our findings are the first to demonstrate DILP signaling originating in therenal tubules and that this signaling is under control of stress-induced release of peptide hormone.

Keyword
Insulin signaling, peptide signaling, insulin, stress
National Category
Biological Sciences
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-62505 (URN)10.1371/journal.pone.0019866 (DOI)000290440200031 ()
Funder
Swedish Research Council, 621-2007-6500
Available from: 2011-09-21 Created: 2011-09-21 Last updated: 2017-12-08Bibliographically approved
2. Regulation of insulin-producing cells in the adult Drosophila brain via the tachykinin peptide receptor DTKR
Open this publication in new window or tab >>Regulation of insulin-producing cells in the adult Drosophila brain via the tachykinin peptide receptor DTKR
Show others...
2011 (English)In: Journal of Experimental Biology, ISSN 0022-0949, E-ISSN 1477-9145, Vol. 214, 4201-4208 p.Article in journal (Refereed) Published
Abstract [en]

Drosophila insulin-like peptides (DILPs) play important hormonal roles in the regulation of metabolic carbohydrates and lipids, but also in reproduction, growth, stress resistance and aging. In spite of intense studies of insulin signaling in Drosophilag the regulation of DILP production and release in adult fruit flies is poorly understood. Here we investigated the role of Drosophila tachykinin-related peptides (DTKs) and their receptors, DTKR and NKD, in the regulation of brain insulin-producing cells (IPCs) and aspects of DILP signaling. First, we show DTK-immunoreactive axon terminations close to the presumed dendrites of the IPCs, and DTKR immunolabeling in these cells. Second, we utilized targeted RNA interference to knock down expression of the DTK receptor, DTKR, in IPCs and monitored the effects on Dilp transcript levels in the brains of fed and starved flies. Dilp2 and Dilp3, but not Dilp5, transcripts were significantly affected by DTKR knockdown in IPCs, both in fed and starved flies. Both Dilp2 and Dilp3 transcripts increased in fed flies with DTKR diminished in IPCs whereas at starvation the Dilp3 transcript plummeted and Dilp2 increased. We also measured trehalose and lipid levels as well as survival in transgene flies at starvation. Knockdown of DTKR in IPCs leads to increased lifespan and a faster decrease of trehalose at starvation but has no significant effect on lipid levels. Finally, we targeted the IPCs with RNAi or ectopic expression of the other DTK receptor, NKD, but found no effect on survival at starvation. Our results suggest that DTK signaling, via DTKR, regulates the brain IPCs.

National Category
Zoology
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-65951 (URN)10.1242/jeb.062091 (DOI)000297684200020 ()22116763 (PubMedID)
Available from: 2011-12-16 Created: 2011-12-16 Last updated: 2017-12-08Bibliographically approved
3. Insulin Signaling, Lifespan and Stress Resistance Are Modulated by Metabotropic GABA Receptors on Insulin Producing Cells in the Brain of Drosophila
Open this publication in new window or tab >>Insulin Signaling, Lifespan and Stress Resistance Are Modulated by Metabotropic GABA Receptors on Insulin Producing Cells in the Brain of Drosophila
Show others...
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.

National Category
Biological Sciences
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-53298 (URN)10.1371/journal.pone.0015780 (DOI)000285793600039 ()21209905 (PubMedID)
Available from: 2011-01-21 Created: 2011-01-21 Last updated: 2017-12-11Bibliographically approved
4. Insulin-producing cells in the Drosophila brain co-localize a satiety-inducing cholecystokinin-like peptide, DSK
Open this publication in new window or tab >>Insulin-producing cells in the Drosophila brain co-localize a satiety-inducing cholecystokinin-like peptide, DSK
(English)Manuscript (preprint) (Other academic)
Keyword
Insulin, peptide signaling, feeding, satiety
National Category
Biological Sciences
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-62508 (URN)
Funder
Swedish Research Council, 621-2007-6500
Available from: 2011-09-21 Created: 2011-09-21 Last updated: 2014-10-13

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