Brainstem GABA neurons orchestrate feeding and body weight
Lead Research Organisation:
University of Aberdeen
Department Name: Rowett Institute of Nutrition and Health
Abstract
The average person living in the UK today is overweight or obese. The reason this is important is because poor diet and excess body fat commonly have a detrimental impact on health. Obesity increases the risk of developing multiple diseases and dying from COVID-19. Obesity also shortens lifespan by nearly a decade, and costs the UK £5.8 billion every year in medical fees. The primary cause of excess body weight is the consumption of more food than the body requires, calories that are then stored in fat. The focus of this application is clarifying the biology behind food choice (why do we prefer cake to cabbage?), meal size and increasing body fat. Another focus of this research is understanding why it can be difficult to lose weight over the long term through dieting. Hunger is commonly the reason it can be difficult to stick to a diet or to keep the weight off. Here we examine a new way to suppress or diminish hunger to help promote long term weight loss. Our focus is on the brain because it is the master coordinator of hunger, employing discrete interwoven circuits to continually appraise and respond to changes in energy availability taken in from food. A principal intersection within this network is the part of the brain called the nucleus of the solitary tract (NTS). Digested nutrients from food in the bloodstream, hormones from our organs and other signals converge within the NTS to inform the brain about our energy status. The NTS integrates this information and forwards a decision to other parts of the brain that control hunger and fullness that then prompt our behaviour (e.g. feel hungry and find food or feel full and stop eating). However, discoveries in this direction have been hindered by a lack of precise tools to understand how hunger, appetite and body weight are controlled. Recent technological advances now provide a means to overcome this obstacle, affording a way to discover how the brain works to monitor energy levels (low or high) to then instruct behaviour (to eat or not to eat), which influences body weight. We can now uncover the location of the chemicals made by the brain that influence our decisions about which foods we choose to eat, how much food we eat and whether these calories are then used or stored in body fat. We think that a chemical called GABA, which our brain makes to typically turn other cells off, works to turn off hunger. Specifically, we believe that GABA made in the NTS receives information from the body when we are eating food and then transmits this information to remove the feeling of hunger so we stop eating. Our initial work on GABA in the NTS supports this idea. Using a combination of state of the art techniques, we will test the function of this specific source of GABA in hunger and body fat in the proposed research programme. This work is important because we believe we have found an essential way that the brain controls hunger, food choice and body weight. We anticipate that these studies will provide fundamental insight into the biological underpinnings of appetite, food choice, body weight and body fat, findings relevant to the prevention and treatment of obesity.
Technical Summary
Obesity is now one of the key challenges facing human health. The national prevalence of obesity emphasises the need for a greater understanding of the physiological mechanisms underlying hunger, feeding behaviour and body fat accrual. On the basis of our preliminary data, we hypothesise the GABA subpopulation of neurons within the brainstem nucleus of the solitary tract (NTS) sense and respond to the ingestion of food to control hunger. Further, we hypothesise that GABA NTS neuron responsiveness to feeding is diminished with obesity, permitting the over-consumption of food. We will test this hypothesis using in vivo fibre photometry to perform the first live recordings of GABA NTS neuron activity in mice as they respond to hunger and food stimuli while lean, obese and following the reversal of obesity. We will also undertake the first targeted manipulation of GABA NTS neuron activity to determine whether activating these neurons treats obesity by decreasing hunger, food intake and body weight, whereas preventing GABA NTS production promotes obesity by increasing hunger, food intake and body weight. We will examine the brain circuit through which these effects are achieved by stimulating or inhibiting GABA NTS release specifically within the homeostatic brain region the arcuate nucleus of the hypothalamus (ARC) and monitoring subsequent behaviour and the activity of hunger neurons. These studies have the potential to clarify a new circuit through which the brain controls hunger, feeding (food choice and meal size) and body weight/body fat. Thereby, this programme of research will offer important insight into the discrete neuronal circuits governing hunger, ingestive behaviour, food choice, body weight and body fat accumulation. Given the pervasiveness of obesity within the global community and the resulting socio-medical ramifications, deciphering the neuronal circuits governing the physiological control of ingestive behaviour and body fat is essential.
Publications
Imoesi PI
(2023)
Control by the brain of vitamin A homeostasis.
in iScience
Lionikas A
(2023)
Stanniocalcin-2 inhibits skeletal muscle growth and is upregulated in functional overload-induced hypertrophy.
in Physiological reports
Martinez De Morentin P
(2023)
A brainstem to hypothalamic arcuate nucleus GABAergic circuit drives feeding
Martinez De Morentin P
(2022)
Molecular mechanisms of appetite control via 5-HT1B receptors
in Proceedings of the Nutrition Society
Martinez De Morentin P
(2022)
Role of brain serotonin in age-related decline in physical activity in mice
in Proceedings of the Nutrition Society
Martynova Y
(2022)
Function of neuropeptide Y within the nucleus of the solitary tract in food intake
in Proceedings of the Nutrition Society
Najm Al-Halboosi DA
(2023)
Modulation of GABA release by 5-HT1B receptors: An interplay with AMPA-receptors and voltage-gated Ca2+ channels.
in Neuropharmacology
Wagner S
(2022)
Function of the nucleus of the solitary tract in the therapeutic effect of obesity medication lorcaserin
in Proceedings of the Nutrition Society
Wagner S
(2023)
Obesity medication lorcaserin activates brainstem GLP-1 neurons to reduce food intake and augments GLP-1 receptor agonist induced appetite suppression.
in Molecular metabolism
Description | Helmholtz SAB |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | Changes are just being implemented, so no impact yet. |
Description | Ongoing Keystone Conference Scientific Advisory Board |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | ISSF Wellcome Trust |
Amount | £25,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2022 |
End | 03/2023 |
Description | Giles Yeo |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We examined the in vivo role of a distinct subsets of neurons within the nucleus of the solitary tract (NTS) in feeding behaviour and insulin sensitivity. |
Collaborator Contribution | The Yeo lab examined the ex vivo characteristics of the distinct subsets of NTS neurons by cell sorting and profiling them with microarray and PCR. |
Impact | the work has been presented at the academic meetings listed under the 'engagement' section and has led to a publication https://www.molecularmetabolism.com/archive/past-issues/volume-43-january-2021/article/article/30706/index.html |
Start Year | 2019 |
Description | Stefan Trapp, University College London |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This project investigates the therapeutic effect of obesity medication lorcaserin and whether it requires nucleus of the solitary tract (NTS) glucagon like peptide 1 (GLP-1) to reduce food intake. A proportion of NTS GLP-1 receptors are GABAergic. This collaboration was initiated at the 2018 Neurobiology of Obesity (NOS) conference, funded by a MRC Discovery grant. We are expert in obesity medication lorcaserin and collaborator Stefan Trapp is expert in brain GLP-1. We provided the hypothesis to investigate - whether lorcaserin employs the brain neuropeptide GLP-1 to produce its therapeutic effect. We tested this hypothesis using a variety of different methodological approaches. |
Collaborator Contribution | The Trapp lab: 1. Examined whether GLP-1 knockdown attenuates lorcaserin's anorectic effect 2. Provided the Heisler lab with research tools to examine the ex vivo effect of lorcaserin in the brainstem. |
Impact | Multiple scientific presentations and a publication. https://www.molecularmetabolism.com/archive/past-issues/volume-43-january-2021/article/article/30706/index.html |
Start Year | 2018 |
Description | Invited Talk - Swiss Winter conference on Ingestive Behaviour |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Approximately 80 academics, students and members from industry attended the conference and my invited talk. The format of the talk included a good period for discussion where ideas were exchanged. This led to discussions of a new collaboration with Tune Pers's group, Novo Nordisk Foundation for Center for Basic Metabolic Research. Discussions with industry Research Diets also occurred. Requests were made for involvement in a future activity. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.winter-ingestion.uzh.ch/en.html |
Description | Invited Talk, University of Leeds |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | Roughly 250 people from the University of Leeds (students and academic staff) attended my invited School of Biomedical Sciences Seminar. The talk I gave was entitled 'New insights into the brain control of appetite'. Host: Beatrice Filippi. the talk sparked lively questions and discussions. During the Q&A, participants reported the attainment of new ideas. |
Year(s) Of Engagement Activity | 2023 |
Description | Invited talk - 3rd International Conference on Precision Nutrition and Metabolism in Public Health and Medicine |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Approximately 100 international academics attended the 3rd International Conference on Precision Nutrition and Metabolism in Public Health and Medicine and my invited talk. Impacts from the meeting include questions and discussion with other academics and delegates from industry, including AstraZeneca. Potential collaborative work was discussed. Other impacts include invitation to be an organiser of the meeting in 2024. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.aegeanconferences.org/src/App/conferences/view/160 |
Description | Invited talk - Edinburgh Diabetes Conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Approximately 100 people attended the Edinburgh Diabetes conference. My invited talk sparked discussion and questions and the audience reported changing views. A collaborative work arose from the meeting with Prof Robert Semple. |
Year(s) Of Engagement Activity | 2022 |
Description | Invited talk and laboratory visit - Industry Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Industry/Business |
Results and Impact | Approximately 60 people attended a meeting where I gave an invited talk and gave a tour of my laboratory. Attendees ranged from members of industry, Scottish parliament and other academics and students. The presentation sparked discussion and questions about our BBSRC funded research programme and allowed a hands-on view of data through the microscope. Discussions were had with major Pharma about potential collaborative work. |
Year(s) Of Engagement Activity | 2023 |
Description | Poster presentation - Europhysiology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation of collaborative work by Stefan Trapp's group. Our collaborative work is now published in Molecular Metabolism (2023). |
Year(s) Of Engagement Activity | 2022 |
URL | https://europhysiology2022.org |
Description | Presentation - Scottish Cardiovascular Forum |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | PDRA on grant presented data generated to date to the forum audience. This led to discussions and reports of increased interest in the subject area. |
Year(s) Of Engagement Activity | 2023 |
Description | School visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 3 classes of primary school children visited the Rowett Institute where we told the student about the effect of nutrition on health. We also explained the discovery of insulin 100 years ago. The children engaged in activities, make scientific badges and received tours (I led these events). the impact was children reporting changing views about nutrition. |
Year(s) Of Engagement Activity | 2022 |
Description | School visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | PDRA on grant attended local school to discuss science. Students reported interest in the area. |
Year(s) Of Engagement Activity | 2023 |
Description | Workshop with lab tour - British Heart Foundation and Politicians |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | An event was organised to showcase metabolic and cardiovascular research at the University of Aberdeen. Invited attendees included politicians, the British Heart Foundation, members from patient groups and other academics, including students. We provided delegates with a tour of our laboratory where we discussed our BBSRC funded research. This sparked questions and discussion. |
Year(s) Of Engagement Activity | 2023 |
Description | invited talk - British Society for Neuroendocrinology and International Congress of Neuroendocrinology |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Approximately 150 people attended the invited talk with international reach. This sparked quite a lot of discussion afterwards. Researcher on grant who has contributed significantly (Pablo Martinez de Morentin) was approached and ultimately offered a Lectureship specifically related to his contribution to the research programme. other impacts include being invited to organise the 2024 meeting. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.neuroendo.org.uk/page.php?item_name=BNG+BSN+Annual+Meetings |
Description | invited talk - Danish Diabetes Academy |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Approximately 150 people attended the annual Dutch Translational Metabolism Conference where I gave an invited talk. This sparked questions and discussions afterwards that led to people changing views and learning new things. I also participated in an event where delegates were asked to guess things about me (which led to a prize) and a speed-dating networking event to allow people to speak with me directly to find out more about my research. |
Year(s) Of Engagement Activity | 2022 |
URL | https://ddeacademy.dk/events |