How the brain controls food intake: the emerging role of the brain GLP-1 system in energy balance and autonomic control
Lead Research Organisation:
Imperial College London
Department Name: Surgery and Cancer
Abstract
Obesity, diabetes and co-morbidities, such as hypertension, are a serious health burden for the patient and a strain on public resources. Promising drugs that might be beneficial for the treatment of these conditions are glucagon-like peptide 1 (GLP-1) analogues. GLP-1 is a hormone that is secreted from the gut after a meal. It is also produced in the brain. Its principal role is to improve the digestion of sugars, and to generate the sensation of fullness, or satiety. The aim of our project is to improve our knowledge of the relative importance of the brain and gut GLP-1 signalling in the control of blood sugar and food intake, and to clarify whether GLP-1 analogues, which are already in clinical use, activate the brain GLP-1 system.
Neurons that produce GLP-1 have been found in the brainstem. These cells send a network of nerve fibres to many parts of the brain, including the hypothalamus, a brain region implicated in the regulation of appetite. We hypothesise that it is GLP-1 released from these brainstem cells that mediates the satiety effects, some of the beneficial effects on blood glucose control, and further functions that are less well understood, such as in cardiovascular control, developing of hypertension, nausea and vomiting, and learning and memory. The proposed research will clarify the exact role of GLP-1 neurons in these effects and thus validate their importance as a drug target for treatment of metabolic disease.
We will use a gene therapy approach where new genes are delivered to GLP-1 cells in specific areas of the brain. These genes will produce proteins allowing cell-specific suppression (or alternatively increases) of the activity of GLP-1 cells with unprecendented temporal and spatial resolution. By measuring the effects of inhibiting or increasing activity of specific GLP-1-expressing cells on blood glucose control, food intake and behaviour, we will be able to tease out the exact physiological function played by GLP-1-expressing central neurons.
The primary aim of our project is to improve knowledge on the interaction between peripheral and central GLP-1 receptor activation. From this work we will learn whether interference with brain GLP-1 release is an important target for the treatment of obesity, diabetes and co-morbidities. These data will provide further insight into the clinical benefit of GLP-1-based treatments, possibly not only for patients with diabetes, but more generally in metabolic disease. Furthermore, it will provide information on the cause of undesired side effects such as nausea. Since GLP-1 analogues are already on the market for the treatment of type 2 diabetes in overweight patients, we expect that the knowledge from this project will feed into drug development and formulation, and thus an influence on therapy could be hoped for within 10 years.
Neurons that produce GLP-1 have been found in the brainstem. These cells send a network of nerve fibres to many parts of the brain, including the hypothalamus, a brain region implicated in the regulation of appetite. We hypothesise that it is GLP-1 released from these brainstem cells that mediates the satiety effects, some of the beneficial effects on blood glucose control, and further functions that are less well understood, such as in cardiovascular control, developing of hypertension, nausea and vomiting, and learning and memory. The proposed research will clarify the exact role of GLP-1 neurons in these effects and thus validate their importance as a drug target for treatment of metabolic disease.
We will use a gene therapy approach where new genes are delivered to GLP-1 cells in specific areas of the brain. These genes will produce proteins allowing cell-specific suppression (or alternatively increases) of the activity of GLP-1 cells with unprecendented temporal and spatial resolution. By measuring the effects of inhibiting or increasing activity of specific GLP-1-expressing cells on blood glucose control, food intake and behaviour, we will be able to tease out the exact physiological function played by GLP-1-expressing central neurons.
The primary aim of our project is to improve knowledge on the interaction between peripheral and central GLP-1 receptor activation. From this work we will learn whether interference with brain GLP-1 release is an important target for the treatment of obesity, diabetes and co-morbidities. These data will provide further insight into the clinical benefit of GLP-1-based treatments, possibly not only for patients with diabetes, but more generally in metabolic disease. Furthermore, it will provide information on the cause of undesired side effects such as nausea. Since GLP-1 analogues are already on the market for the treatment of type 2 diabetes in overweight patients, we expect that the knowledge from this project will feed into drug development and formulation, and thus an influence on therapy could be hoped for within 10 years.
Technical Summary
This proposal aims at characterising the exact physiological role of GLP-1 expressing neurons in the control of energy balance and autonomic functions. We will experimentally silence or activate GLP-1-expressing neuronal populations in vivo by using viral gene transfer. Specific targeting will be achieved by combining a transgenic mouse line that expresses Cre-recombinase selectively in cells that express GLP-1 or glucagon, with viral expression vectors that are only active in cells expressing Cre-recombinase (FLEX-switch technique). The adeno-associated virus (AAV)-based vectors are injected stereotaxically into the brain region containing GLP-1-expressing neurons and 2-5 weeks after the infections the animals will be tested for effects of GLP-1 neuron modulation on food intake, blood glucose control, cardiovascular and circadian activities. AAV vectors produced for this purpose will include those that inactivate or ablate GLP-1 cells permanently (Tetanus toxin light chain; Diphteria toxin A subunit), and those that inactivate GLP-1 cells transiently (Allatostatin receptor; DREADD hM4D) or activate GLP-1 neurons transiently (Channelrhodopsin2, DREADD hM3Dq), when the appropriate agonist is applied (allatostatin, clozapine-N-oxide or light, respectively). Generation of these tools will also greatly facilitate physiological in vivo studies of other specific cell populations in the CNS.
Food and water intake will be monitored using metabolic cages, blood glucose control will be evaluated with oral and intraperitoneal glucose tolerances tests, cardiovascular and respiratory activities will be assessed using standard physiological monitoring in anesthetised animals.
Our results will further define the physiological role of the GLP-1 neurons and provide crucial data on the usefulness of a GLP-1 based therapy for metabolic disease. They will also address the question whether overactivation of this system leads to emesis as observed with GLP-1 injection.
Food and water intake will be monitored using metabolic cages, blood glucose control will be evaluated with oral and intraperitoneal glucose tolerances tests, cardiovascular and respiratory activities will be assessed using standard physiological monitoring in anesthetised animals.
Our results will further define the physiological role of the GLP-1 neurons and provide crucial data on the usefulness of a GLP-1 based therapy for metabolic disease. They will also address the question whether overactivation of this system leads to emesis as observed with GLP-1 injection.
Planned Impact
The basic research we propose here is likely to significantly increase understanding of how GLP-1 affects energy balance and cardiovascular control. We expect these results to be of considerable nterest to the pharmaceutical industry. This is particularly likely becauseGLP-1 analogues are already in clinical use for the treatment of overweight diabetics. Indeed, Astra Zeneca agreed to sponsor a symposium on GLP-1 at the recent FEPS meeting in Istanbul that ST organised in collaboration with Frank Reimann from Cambridge University. Any intellectual property arising from this research grant will be exploited through Imperial College Innovations Ltd, the College's technology transfer company.
A benefit to the general population, in terms of improvements in healthcare, might be possible over a time-course of 10 years if our findings influence the availability of GLP-1 therapy for diabetic and for obese patients. Additionally, our research might identify new treatment strategies for metabolic disease, which could hopefully enter clinical practice over a 10-15 year time-course. This again would elicit interest from the pharmaceutical industry. Currently ~10% of the NHS budget (£9billion) is spent on the 2.6 million diabetics in the UK. Diabetes UK predicts this number to rise to 4 million by 2025, mainly due to an increased incidence of obesity, driven by increasingly sedentary lifestyles. In 2009 more than 60% of the adult UK population were overweight. The complications of these diseases include stroke, retinopathy, neuropathy, renal failure, cardiovascular disease and cancer. The increased prevalence of diabetes, obesity and co-morbidities was recently predicted to contribute to a lowered overall life expectancy in the UK (http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/diabetes-may-cause-first-fall-in-life-expectancy-for-200-years-966914.html) for the first time in 200 years. GLP-1 analogues show great potential in the treatment of type 2 diabetics mainly due to their actions as insulin secretagogues and positive trophic effect on beta-cell mass. The anorexic effect of GLP-1 is mediated by central actions and so might be some of the insulin secretagogue effect. Since GLP-1 has various central effects (including induction of nausea and vomiting, in addition to satiety) exogenous application might be counterproductive. Our study of the endogenous source of GLP-1 in brain will educate us about the different pathways involved and thus clarify the role of central GLP-1 in satiety and blood glucose control. In particular, this work will address roadblocks in diabetes research as identified recently by the European Commission's Support Action "DIAMAP: A Road Map for Diabetes in Europe" (http://www.diamap.eu/) including "Determine central nervous master switches that control food intake and energy expenditure", which is identified as lacking "collaboration of researchers in related fields" and "available in vivo methodology and imaging techniques", both of which we are addressing with this proposal.
A benefit to the general population, in terms of improvements in healthcare, might be possible over a time-course of 10 years if our findings influence the availability of GLP-1 therapy for diabetic and for obese patients. Additionally, our research might identify new treatment strategies for metabolic disease, which could hopefully enter clinical practice over a 10-15 year time-course. This again would elicit interest from the pharmaceutical industry. Currently ~10% of the NHS budget (£9billion) is spent on the 2.6 million diabetics in the UK. Diabetes UK predicts this number to rise to 4 million by 2025, mainly due to an increased incidence of obesity, driven by increasingly sedentary lifestyles. In 2009 more than 60% of the adult UK population were overweight. The complications of these diseases include stroke, retinopathy, neuropathy, renal failure, cardiovascular disease and cancer. The increased prevalence of diabetes, obesity and co-morbidities was recently predicted to contribute to a lowered overall life expectancy in the UK (http://www.independent.co.uk/life-style/health-and-wellbeing/health-news/diabetes-may-cause-first-fall-in-life-expectancy-for-200-years-966914.html) for the first time in 200 years. GLP-1 analogues show great potential in the treatment of type 2 diabetics mainly due to their actions as insulin secretagogues and positive trophic effect on beta-cell mass. The anorexic effect of GLP-1 is mediated by central actions and so might be some of the insulin secretagogue effect. Since GLP-1 has various central effects (including induction of nausea and vomiting, in addition to satiety) exogenous application might be counterproductive. Our study of the endogenous source of GLP-1 in brain will educate us about the different pathways involved and thus clarify the role of central GLP-1 in satiety and blood glucose control. In particular, this work will address roadblocks in diabetes research as identified recently by the European Commission's Support Action "DIAMAP: A Road Map for Diabetes in Europe" (http://www.diamap.eu/) including "Determine central nervous master switches that control food intake and energy expenditure", which is identified as lacking "collaboration of researchers in related fields" and "available in vivo methodology and imaging techniques", both of which we are addressing with this proposal.
Organisations
- Imperial College London (Lead Research Organisation)
- Cochin Institute (Collaboration)
- University of Pisa (Collaboration)
- University of Milan (Collaboration)
- University College London (Collaboration)
- University of Gothenburg (Collaboration)
- Ben-Gurion University of the Negev (Collaboration)
- Novo Nordisk (Collaboration)
- Flinders University (Collaboration)
- Institute of Genetics and Molecular and Cellular Biology (IGBMC) (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- Open University of Israel (Collaboration)
- AstraZeneca (Collaboration)
- University of Geneva (Collaboration)
- Florida State University (Collaboration)
- Yale University (Collaboration)
- University of Toronto (Collaboration)
- University of Alberta (Collaboration)
- University of Bristol (Collaboration)
- University of Cambridge (Project Partner)
Publications
Anesten F
(2016)
Preproglucagon neurons in the hindbrain have IL-6 receptor-a and show Ca2+ influx in response to IL-6.
in American journal of physiology. Regulatory, integrative and comparative physiology
Cork SC
(2015)
Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain.
in Molecular metabolism
Holt MK
(2016)
The physiological role of the brain GLP-1 system in stress.
in Cogent biology
Llewellyn-Smith IJ
(2015)
Spinally projecting preproglucagon axons preferentially innervate sympathetic preganglionic neurons.
in Neuroscience
Richards P
(2014)
Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model.
in Diabetes
Soedling H
(2015)
Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells.
in Molecular metabolism
Thiebaud N
(2016)
The incretin hormone glucagon-like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage-dependent potassium channel
in The Journal of Physiology
Trapp S
(2013)
The gut hormone glucagon-like peptide-1 produced in brain: is this physiologically relevant?
in Current opinion in pharmacology
Trapp S
(2015)
PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation.
in American journal of physiology. Regulatory, integrative and comparative physiology
Trapp S
(2022)
New developments in the prospects for GLP-1 therapy.
in British journal of pharmacology
Description | BHF studentship |
Amount | £114,000 (GBP) |
Funding ID | FS/14/43/30960 |
Organisation | Loughborough University |
Department | British Heart Foundation National Centre for Physical Activity and Health (BHFNC) |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2014 |
End | 09/2017 |
Description | Cardiac vagus and exercise in health and disease (renewal) |
Amount | £1,022,603 (GBP) |
Funding ID | RG/19/5/34463 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 03/2025 |
Description | Neuroendocrine Integration of Satiety and Food Reward |
Amount | $1,727,512 (USD) |
Funding ID | DK095757 |
Organisation | National Institutes of Health (NIH) |
Sector | Public |
Country | United States |
Start | 04/2019 |
End | 05/2021 |
Description | Preproglucagon neuron activation as a novel therapeutic approach for obesity and metabolic disease |
Amount | € 93,400 (EUR) |
Organisation | European Association for the Study of Diabetes (EASD) |
Department | European Foundation for the Study of Diabetes (EFSD) |
Sector | Academic/University |
Country | Germany |
Start | 08/2021 |
End | 08/2022 |
Description | AMPK in central control of hepatic glucose production |
Organisation | University of Toronto |
Country | Canada |
Sector | Academic/University |
PI Contribution | Generation and use of adenoviral constructs |
Impact | Publication in Diabetes 2010 (x2) |
Start Year | 2008 |
Description | Cardiac preconditioning via vagal nerve activity |
Organisation | University College London |
Department | Division of Biosciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | in vitro analysis of vagal activity |
Collaborator Contribution | provided model of hear failure |
Impact | Publications: Mastitskaya et al. (2012) Cardiovascular Research 95, 487-494. Machhada et al. (2015) Heart Rhythm 12, 2285-2293. |
Start Year | 2011 |
Description | Collaboration on GLP-1 analogue action in mouse |
Organisation | Novo Nordisk |
Country | Denmark |
Sector | Private |
PI Contribution | Analyse central effects of Novo Nordisk depeloped GLP-1 analogues |
Collaborator Contribution | provide chemical compounds |
Impact | not published yet |
Start Year | 2019 |
Description | Collaboration with Linda Rinaman to investigate central GLP-1 cross-species |
Organisation | Florida State University |
Country | United States |
Sector | Academic/University |
PI Contribution | Experimentation into mouse GLP-1 system to establish absence of GLP-1 receptors on GLP-1 producing neurons |
Collaborator Contribution | Similar experimentation on rat. |
Impact | Research paper (PMID: 30019398) Follow up funding from NIH 2R01DK095757 |
Start Year | 2017 |
Description | Conditional knockout mice |
Organisation | Cochin Institute |
Country | France |
Sector | Academic/University |
PI Contribution | Generation of tissue specifi KO mice |
Impact | Publication in Diabetologia, 2010 (Sun et al) |
Description | Crosstalk between GLP-1 and Interleukin-6 in brain |
Organisation | University of Gothenburg |
Department | Department of Physiology |
Country | Sweden |
Sector | Academic/University |
PI Contribution | Functional analysis of the response of GLP-1 producing neurons to interleukin; expertise with transgenic mice allowing identification and characterisation of GLP-1 producing and GLP-1 receptor expressing cells |
Collaborator Contribution | Expertise with interleukin in the brain |
Impact | 10.1152/ajpregu.00383.2015 10.1159/000499693 |
Start Year | 2015 |
Description | D Bosco (Université de Genève) |
Organisation | University of Geneva |
Department | Faculty of Diabetes |
Country | Switzerland |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 |
Start Year | 2013 |
Description | Denton |
Organisation | University of Bristol |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | manuscript (in press) Denton RM et al Biochem J 2016 |
Start Year | 2014 |
Description | Denton |
Organisation | University of Pisa |
Country | Italy |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 |
Start Year | 2014 |
Description | Functional characterisation of GLP-1 neurons |
Organisation | University of Cambridge |
Department | Cambridge Institute for Medical Research (CIMR) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Devised experiments, conducted experiments, wrote publications |
Collaborator Contribution | Provision of transgenic mice that allows identification of GLP-1 neurons in vitro. |
Impact | Publications describing critical electrical and molecular properties of GLP-1 neurons (20522593, 21885869) |
Start Year | 2006 |
Description | GLP-1 action in mesolimbic system |
Organisation | Florida State University |
Country | United States |
Sector | Academic/University |
PI Contribution | -Electrophysiological characterisation of GLP-1 receptor expressing cells in the bed nucleus of the stria terminalis. -circuit mapping of GLP-1 projections to GLP-1R neurons and of GLP-1R cell projections from the bed nucleus of the stria terminalis |
Collaborator Contribution | Analysis of GLP-1 effects in the bed nucleus of the stria terminalis on food intake |
Impact | 10.1016/j.neuropharm.2017.12.007 follow-up funding from NIH: 2R01DK095757 |
Start Year | 2016 |
Description | GLP-1 in olfactory system |
Organisation | Florida State University |
Department | Department of Biological Science |
Country | United States |
Sector | Academic/University |
PI Contribution | Providing morphological and cytochemical analysis of olfactory bulb tissue from transgenic mice |
Collaborator Contribution | Electrophysiological analysis of mitral cell activity under GLP-1 |
Impact | Publication in Journal of Physiology Publication in Scientific Reports |
Start Year | 2013 |
Description | Generator of b-cell specfic knock-out mice for PASK |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | Design of PASK flox'd mice |
Impact | None as yet |
Start Year | 2009 |
Description | Gerald Gradwohl (IGBMC) |
Organisation | Institute of Genetics and Molecular and Cellular Biology (IGBMC) |
Country | France |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | Piccard et al - http://www.ncbi.nlm.nih.gov/pubmed/25497096 |
Start Year | 2015 |
Description | Immunocytochemical characterisation of GLP-1 neurons |
Organisation | Flinders University |
Country | Australia |
Sector | Academic/University |
PI Contribution | provision of fixed tissue from transgenic mice; intellectual lead |
Collaborator Contribution | Expertise in immunocytochemistry |
Impact | Publication that produces a detailed description of GLP-1 neuron distribution and projections in brain (21329743) |
Start Year | 2009 |
Description | James Shapiro (Alberta) |
Organisation | University of Alberta |
Country | Canada |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 |
Start Year | 2014 |
Description | Lorenzo Piemouti (Milan) |
Organisation | University of Milan |
Country | Italy |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al - PMID: 24740569 Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores. Marmugi A et al - PMID: 26822088 |
Start Year | 2014 |
Description | Piero Marchetti (Pisa) |
Organisation | University of Pisa |
Country | Italy |
Sector | Academic/University |
PI Contribution | experiments for publications |
Collaborator Contribution | experiments for publications |
Impact | Sorcin links pancreatic ß cell lipotoxicity to ER Ca2+ stores - Marmugi A et al - PMID: 26822088 Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Gerber PA et al PMID: 24865615 Incretin-modulated beta cell energetics in intact islets of Langerhans. Hodson DJ et al - PMID: 24766140 ADCY5 couples glucose to insulin secretion in human islets. Hodson DJ et al PMID: 24740569 Lipotoxicity disrupts incretin-regulated human ß cell connectivity. Hodson DJ et al - PMID: 24018562 |
Start Year | 2014 |
Description | Role of AMPK in counter regulation |
Organisation | Yale University |
Country | United States |
Sector | Academic/University |
PI Contribution | Provision of adenoviral constructs |
Impact | None as yet |
Start Year | 2008 |
Description | Sekler |
Organisation | Ben-Gurion University of the Negev |
Country | Israel |
Sector | Academic/University |
PI Contribution | Experiments for research paper |
Collaborator Contribution | Experiments for research paper |
Impact | Publication Pancreatic beta-cell Na+ channels control global Ca2+ signaling and oxidative metabolism by inducing Na+ and Ca2+ responses that are propagated into mitochondria. DOI - 10.1096/fj.13-248161 |
Start Year | 2013 |
Description | Yuval Dor (Israel) |
Organisation | Open University of Israel |
Country | Israel |
Sector | Academic/University |
PI Contribution | Experiments for publications |
Collaborator Contribution | Experiments for publications |
Impact | LKB1 and AMPK differentially regulate pancreatic ß-cell identity - Kone M1 et al - FASEB J. 2014 Nov;28(11):4972-85. doi: 10.1096/fj.14-257667. Epub 2014 Jul 28. Loss of Liver Kinase B1 (LKB1) in Beta Cells Enhances Glucose-stimulated Insulin Secretion Despite Profound Mitochondrial Defects. Swisa A1et al - J Biol Chem. 2015 Aug 21;290(34):20934-46. doi: 10.1074/jbc.M115.639237. Epub 2015 Jul 2. |
Start Year | 2014 |
Description | modulating brainstem neuron activity with viral gene transfer |
Organisation | University College London |
Department | Department of Neuroscience, Physiology and Pharmacology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | in vitro analysis |
Collaborator Contribution | in vivo analysis |
Impact | publications: Marina et al., 2010 Mastitskaya et al., 2012 |
Start Year | 2010 |