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Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT(1A) receptor.
Stockholm University, Faculty of Science, Department of Zoology, Functional Morphology.
Stockholm University, Faculty of Science, Department of Zoology, Functional Morphology.ORCID iD: 0000-0002-1147-7766
2011 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 69, no 3, 471-484 p.Article in journal (Refereed) Published
Abstract [en]

Insulin signaling regulates lifespan, reproduction, metabolic homeostasis, and resistance to stress in the adult organism. In Drosophila, there are seven insulin-like peptides (DILP1-7). Three of these (DILP2, 3 and 5) are produced in median neurosecretory cells of the brain, designated IPCs. Previous work has suggested that production or release of DILPs in IPCs can be regulated by a factor secreted from the fat body as well as by neuronal GABA or short neuropeptide F. There is also evidence that serotonergic neurons may regulate IPCs. Here, we investigated mechanisms by which serotonin may regulate the IPCs. We show that the IPCs in adult flies express the 5-HT(1A), but not the 5-HT(1B) or 5-HT(7) receptors, and that processes of serotonergic neurons impinge on the IPC branches. Knockdown of 5-HT(1A) in IPCs by targeted RNA interference (RNAi) leads to increased sensitivity to heat, prolonged recovery after cold knockdown and decreased resistance to starvation. Lipid metabolism is also affected, but no effect on growth was seen. Furthermore, we show that DILP2-immunolevels in IPCs increase after 5-HT(1A) knockdown; this is accentuated by starvation. Heterozygous 5-HT(1A) mutant flies display the same phenotype in all assays, as seen after targeted 5-HT(1A) RNAi, and flies fed the 5-HT(1A) antagonist WAY100635 display reduced lifespan at starvation. Our findings suggest that serotonin acts on brain IPCs via the 5-HT(1A) receptor, thereby affecting their activity and probably insulin signaling. Thus, we have identified a second inhibitory pathway regulating IPC activity in the Drosophila brain.

Place, publisher, year, edition, pages
2011. Vol. 69, no 3, 471-484 p.
Keyword [en]
5-hydroxytryptamine, Insulin signaling, G-protein-coupled receptor, Lifespan, Stress resistance
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:su:diva-65955DOI: 10.1007/s00018-011-0789-0ISI: 000299091500014PubMedID: 21818550OAI: oai:DiVA.org:su-65955DiVA: diva2:466567
Funder
Swedish Research Council
Available from: 2011-12-16 Created: 2011-12-16 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Regulation of insulin signaling and its developmental and functional roles on peptidergic neurons in the Drosophila central nervous system
Open this publication in new window or tab >>Regulation of insulin signaling and its developmental and functional roles on peptidergic neurons in the Drosophila central nervous system
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Drosophila, eight insulin-like peptides (DILP1-8) are produced and secreted in different locations. They regulate many aspects of development and physiology, such as organism growth, metabolic homeostasis, reproduction, stress resistance and life span. DILP2, 3 and 5 are mainly produced by a cluster of median neurosecretory cells in the brain known as insulin producing cells (IPCs). Here we showed that IPCs are under tight regulation of two G-protein coupled receptors (GPCRs), serotonin receptor 5-HT1A and octopamine receptor OAMB. Genetic manipulations of these two receptors in IPCs affected transcription levels of DILPs, hence altered feeding, carbohydrate levels, and resistance to stress (Paper I and II). Moreover, we showed that the insulin receptor (dInR) is strongly expressed in leucokininergic neurons (LK neurons), and selectively regulates growth of around 300 neuropeptidergic neurons expressing the bHLH transcription factor DIMMED. Overexpression of dInR in DIMM-positive neurons led to substantial neuronal growth, including cell body size, golgi apparatus and nuclear size, while knockdown of dInR had the opposite effect (Paper III). Manipulations of components in the insulin signaling pathway in LK neurons resulted in the similar cell size phenotypes. Furthermore, dInR regulated size scaling of DIMM-postive neurons is nutrient-dependent and partially requires the presence of DIMM (Paper III). Finally, we investigated the roles of DILPs (2, 3, 5 and 7) and LK neurons in regulation of feeding and diuresis at the adult stage (Paper IV).  In summary, we have identified two more regulators for IPC activity and demonstrated developmental roles of  DILPs and dInR in regulating neuronal size. Moreover, DILPs regulate water homeostasis together with a diuretic hormone leucokinin and as a consequence affects feeding behavior.

Place, publisher, year, edition, pages
Stockholm: Department of Zoology, Stockholm University, 2013. 40 p.
Keyword
Insulin, serotonin, octopamine, insulin receptor, Dimm, neuropeptide
National Category
Zoology
Research subject
Functional Zoomorphology
Identifiers
urn:nbn:se:su:diva-96050 (URN)978-91-7447-817-4 (ISBN)
Public defence
2013-12-13, William-Olssonsalen, Geovetenskapens hus, Svante Arrheniusvägen 14, Stockholm, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: In press. Paper 4: Manuscript.

Available from: 2013-11-21 Created: 2013-11-08 Last updated: 2016-01-04Bibliographically approved

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