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Regulation of insulin producing cells, stress responses and metabolism in Drosophila
Stockholm University, Faculty of Science, Department of Zoology. (Functional Zoomorphology)
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 [en]
Insulin signaling, Drosophila melanogaster, peptide hormones, neuropeptides, GABA
National Category
Cell Biology
Research subject
Functional Zoomorphology
Identifiers
URN: urn:nbn:se:su:diva-80518ISBN: 978-91-7447-582-1 (print)OAI: oai:DiVA.org:su-80518DiVA: diva2:556121
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
List of papers
1. 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
2. Metabolic stress responses in Drosophila are modulated by brain neurosecretory cells that produce multiple neuropeptides
Open this publication in new window or tab >>Metabolic stress responses in Drosophila are modulated by brain neurosecretory cells that produce multiple neuropeptides
Show others...
2010 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 5, no 7, e11480- p.Article in journal (Refereed) Published
Abstract [en]

In Drosophila, neurosecretory cells that release peptide hormones play a prominent role in the regulation of development, growth, metabolism, and reproduction. Several types of peptidergic neurosecretory cells have been identified in the brain of Drosophila with release sites in the corpora cardiaca and anterior aorta. We show here that in adult flies the products of three neuropeptide precursors are colocalized in five pairs of large protocerebral neurosecretory cells in two clusters (designated ipc-1 and ipc-2a): Drosophila tachykinin (DTK), short neuropeptide F (sNPF) and ion transport peptide (ITP). These peptides were detected by immunocytochemistry in combination with GFP expression driven by the enhancer trap Gal4 lines c929 and Kurs-6, both of which are expressed in ipc-1 and 2a cells. This mix of colocalized peptides with seemingly unrelated functions is intriguing and prompted us to initiate analysis of the function of the ten neurosecretory cells. We investigated the role of peptide signaling from large ipc-1 and 2a cells in stress responses by monitoring the effect of starvation and desiccation in flies with levels of DTK or sNPF diminished by RNA interference. Using the Gal4-UAS system we targeted the peptide knockdown specifically to ipc-1 and 2a cells with the c929 and Kurs-6 drivers. Flies with reduced DTK or sNPF levels in these cells displayed decreased survival time at desiccation and starvation, as well as increased water loss at desiccation. Our data suggest that homeostasis during metabolic stress requires intact peptide signaling by ipc-1 and 2a neurosecretory cells.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-41306 (URN)10.1371/journal.pone.0011480 (DOI)000279637100010 ()
Available from: 2010-07-10 Created: 2010-07-10 Last updated: 2014-10-28Bibliographically approved
3. Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin
Open this publication in new window or tab >>Identified peptidergic neurons in the Drosophila brain regulate insulin-producing cells, stress responses and metabolism by coexpressed short neuropeptide F and corazonin
2012 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 69, no 23, 4051-4066 p.Article in journal (Refereed) Published
Abstract [en]

Insulin/IGF-like signaling regulates the development, growth, fecundity, metabolic homeostasis, stress resistance and lifespan in worms, flies and mammals. Eight insulin-like peptides (DILP1-8) are found in Drosophila. Three of these (DILP2, 3 and 5) are produced by a set of median neurosecretory cells (insulin-producing cells, IPCs) in the brain. Activity in the IPCs of adult flies is regulated by glucose and several neurotransmitters and neuropeptides. One of these, short neuropeptide F (sNPF), regulates food intake, growth and Dilp transcript levels in IPCs via the sNPF receptor (sNPFR1) expressed on IPCs. Here we identify a set of brain neurons that utilizes sNPF to activate the IPCs. These sNPF-expressing neurons (dorsal lateral peptidergic neurons, DLPs) also produce the neuropeptide corazonin (CRZ) and have axon terminations impinging on IPCs. Knockdown of either sNPF or CRZ in DLPs extends survival in flies exposed to starvation and alters carbohydrate and lipid metabolism. Expression of sNPF in DLPs in the sNPF mutant background is sufficient to rescue wild-type metabolism and response to starvation. Since CRZ receptor RNAi in IPCs affects starvation resistance and metabolism, similar to peptide knockdown in DLPs, it is likely that also CRZ targets the IPCs. Knockdown of sNPF, but not CRZ in DLPs decreases transcription of Dilp2 and 5 in the brain, suggesting different mechanisms of action on IPCs of the two co-released peptides. Our findings indicate that sNPF and CRZ co-released from a small set of neurons regulate IPCs, stress resistance and metabolism in adult Drosophila.

Keyword
Insulin signaling, Peptide hormones, Neuropeptides, Drosophila melanogaster
National Category
Cell Biology
Identifiers
urn:nbn:se:su:diva-80362 (URN)10.1007/s00018-012-1097-z (DOI)000310868200015 ()22828865 (PubMedID)
Funder
Swedish Research Council
Available from: 2012-09-18 Created: 2012-09-18 Last updated: 2017-12-07Bibliographically approved
4. A search for reciprocal signaling between insulin and adipokinetic hormone producing cells in Drosophila
Open this publication in new window or tab >>A search for reciprocal signaling between insulin and adipokinetic hormone producing cells in Drosophila
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Insulin signaling in Drosophila regulates major physiological processes such as stress resistance, growth, carbohydrate and lipid metabolism, aging, reproduction and possibly diapause. Adipokinetic hormone (AKH) signaling originating from the corpora cardiaca (CC) cells, is another crucial regulator of hemolymph carbohydrate levels in Drosophila. These two systems are suggested to have opposing effects on lipid and sugar metabolism in Drosophila, reminiscent of the mammalian insulin and glucagon hormones. We studied the possible functional relationship between the insulin producing cells (IPCs) and the CC cells by interfering with insulin receptor (InR) and AKH receptor (AKH-R) expression on these cells. Our experiments revealed increased carbohydrate and lipid levels after knocking down InR in the CC cells. We also showed that diminished InR levels on the IPCs lead to increased starvation resistance, however we did not observe any changes in carbohydrate or lipid levels. So far we can only suggest action of insulins via its receptor on the IPCs and the CC cells, but we do not have conclusive data for AKH action on IPCs or CC cells.

Keyword
Insulin signaling, insulin receptor, adipokinetic hormone receptor, metabolism, peptide hormones, Drosophila melanogaster
National Category
Cell Biology
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-80322 (URN)
Funder
Swedish Research Council
Available from: 2012-09-17 Created: 2012-09-17 Last updated: 2012-09-24Bibliographically approved

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