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Characterization and mapping of Glucagon-like peptide (GLP)-1 and Glucose-dependent insulinotropic polypeptide (GIP) receptor expressing neurons in the brain

English title Characterization and mapping of Glucagon-like peptide (GLP)-1 and Glucose-dependent insulinotropic polypeptide (GIP) receptor expressing neurons in the brain
Applicant Timper Katharina
Number 174371
Funding scheme Return CH Advanced Postdoc.Mobility
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Neurophysiology and Brain Research
Start/End 01.07.2018 - 28.02.2019
Approved amount 73'055.00
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All Disciplines (3)

Discipline
Neurophysiology and Brain Research
Endocrinology
Genetics

Keywords (5)

Brain; Glucagon-like peptide (GLP-1); Feeding behavior; Glucose homeostasis; Obesity

Lay Summary (German)

Lead
Katharina Timper
Lay summary

Die neuesten Zahlen der Gesundheitsentwicklung belegen einen alle Befürchtungen übertreffenden Anstieg der Adipositas (Fettleibigkeit) quer durch sämtliche Bevölkerungsschichten. Fettleibigkeit ist durch das vermehrte Auftreten von Adipositas-assoziierten Erkrankungen wie Typ 2 Diabetes mellitus, Bluthochdruckerkrankungen, Fettstoffwechselstörungen und Krebsleiden gekennzeichnet. Deswegen müssen rasch neue Behandlungsmethoden gefunden werden, um alleine unzureichende Diätmaßnahmen und vermehrte körperliche Aktivität medikamentös zur Therapie des Übergewichtes zu unterstützen. Das Projekt leistet hierzu einen entscheidenden Beitrag.

Eine besondere Bedeutung für die Regulation der Energiehomöostase kommt dem zentralen Nervensystem (ZNS) zu. Neben Leptin und Insulin spielt das Hormon Glucagon-like peptide (GLP)-1 eine wichtige Rolle bei der zentralen Regulation des Energiehaushaltes, der Nahrungsaufnahme, und des Belohnungssystems. GLP-1-Analoga werden im klinischen Alltag bereits breitflächig zur Behandlung von Typ 2 Diabetes und neu auch bei Übergewicht eingesetzt. Unklar ist zum derzeitigen Zeitpunkt, über welche neuronalen Mechanismen und Nervenzellgruppen sowie Mediatoren GLP-1 seine Wirkung entfaltet und welche neuronalen Netzwerke beteiligt sind.

Ziel des vorliegenden Forschungsprojekts ist es, unter Einsatz neuester Techniken, spezifisch GLP-1-responsible Neurone zu aktivieren, um im lebenden Organismus deren Funktion für die Kontrolle des Energiehaushaltes zu untersuchen. Das übergeordnete langfristige Ziel dieser Versuche besteht darin, im lebenden Organismus die neuronalen Schaltkreise zu definieren, welche physiologischerweise GLP-1-Rezeptor-abhängig Energiehaushalt, Glukosestoffwechsel und Belohnungssystem regulieren und deren Veränderung bei Vorliegen einer Adipositas als möglichen Ansatzpunkt neuer, GLP-1-basierter therapeutischer Interventionen für die Fettsuchtbehandlung zu definieren.

Direct link to Lay Summary Last update: 26.06.2018

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Abstract

The expanding epidemic of obesity is a major global socioeconomic burden and is urgently calling for a better understanding of the underlying causes that lead to increased weight gain and its associated metabolic comorbidities like type 2 diabetes and cardiovascular diseases to set the stage for the development of new therapeutic strategies. Obesity is resulting from a dysbalance in caloric intake and energy expenditure, whereby the central nervous system (CNS), that both senses and controls the energy status of the organism, has emerged as an integrating, superordinate master-regulator of whole body energy homeostasis. Distinct neuronal cell populations, within the arcuate nucleus (ARC) of the hypothalamus sense the nutrient status of the organism and integrate hormonal signals, like pancreas-derived insulin and adipocyte-derived leptin, from the periphery to regulate/direct calorie intake, glucose metabolism and energy expenditure. Thereby the arcuate neurons are tightly connected with other specialized neuronal subpopulations within the hypothalamus like the paraventricular nucleus (PVN) and the ventromedial nucleus (VMH) but also with various extrahypothalamic brain regions like the mesolimbic reward system leading to a coordinated behavioral response. However, recent studies pointed towards other, yet underexplored brain regions like the olfactory sensory system as well as non-neuronal structures like astrocytes to act as metabolic sensors in the brain. Therefore it will be of great importance to unravel their contribution to the central regulatory mechanisms of energy homeostasis. Glucagon-like peptide (GLP)-1 is an incretin hormone that is mainly released from entero-endocrine cells in the gut upon nutrient ingestion but is also produced in distinct neuronal populations in the brain. The classical understanding of the incretin action is the stimulation of insulin secretion from pancreatic islets in a glucose-dependent manner. Thereby GLP-1 contributes to the regulation of glucose homeostasis after oral food intake. GLP-1 acts via specific G-protein coupled receptors that are expressed in a wide range of peripheral tissues apart from the pancreatic islets including the CNS. GLP-1 receptors (GLP-1R) are highly expressed in hypothalamic nuclei and mesolimbic areas. In line, recent studies pointed to a crucial role of central GLP-1R signaling in the regulation of feeding, glucose homeostasis and food-related reward behavior. However, the distinct neuronal circuits, especially those interconnecting the hypothalamic nuclei and the mesolimbic system, underlying synaptic plasticity mechanisms and involved neurotransmitters have not or only barely been studied to date. The overall aim of this project is to characterize and discover the role of GLP-1-R expressing neuronal and non-neuronal cell populations in the brain and to unravel the neuronal circuits that are involved in the central GLP-1R-dependent control of feeding, glucose and energy homeostasis. Therefore we employed the Cre-lox system to specifically delete GLP-1R expression in distinct neuronal and astrocytic cell populations of the CNS and to study the resulting effects on energy and glucose homeostasis as well as behavioral aspects. Furthermore, to allow for a specific activation not only of GLP-1R-expressing neurons but also of their effector neurons we will apply optogenetic and chemogenetic approaches to unravel the neurocircuitries that are involved in the transduction of GLP-1 action in the brain. So far, our studies already evolved a crucial role of GLP-1R signaling for the regulation of glucose and energy homeostasis in two, yet unknown, central cell populations: the mitral cells of the olfactory system and astrocytes. The characterization of the connectivity of GLP-1-R expressing neuronal and astrocytic cell populations with neuronal clusters regulating energy homeostasis and the mapping of the neuronal circuits involved is of great importance to understand the role of central GLP-1 action that may pave the way for the development of new therapeutic strategies for the treatment of obesity and associated metabolic diseases.
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