The role of hypothalamic astrocytes in homeostatic regulation of feeding behaviour

Lead Research Organisation: University of Exeter
Department Name: Institute of Biomed & Clinical Science

Abstract

Disturbed regulation of food intake contributes to obesity, which is a major, and growing, public health issue in the U.K. Obesity already affects greater than 25% of the adult population and is costing the NHS an estimated £4.2billion annually. To enable scientists and pharmaceutical companies to develop the most effective therapeutic interventions for diseases like obesity, where the body's mechanisms regulating food intake are not working correctly, it is critical that we develop a thorough and detailed understanding of how food intake is regulated normally.

Mechanisms based within the central nervous system (CNS) contribute pivotally to control of food intake and body weight. Although many brain areas play a role in control of feeding behaviours, a region known as the hypothalamus is vital for orchestrating the regulation of food intake, something that occurs through both nervous and hormonal signalling processes. Basic research, like that proposed here, has already identified critical circuits of nerve cells within the hypothalamus that are vital for the regulation of food intake. These include specific neurons which increase the motivation to eat when they are active and different neurons which can produce the opposite outcome, namely suppressing food intake. Although neurons are the best known cell type within the brain, they are not the most abundant. This distinction falls to non-neuronal cells known as glia. The functional involvement of glia in the regulation of food intake remains poorly understood, although these cells can unquestionably influence other bodily functions. For example, we know an important class of glial cells known as astroglia can directly regulate the activity of hypothalamic nerve circuits that control reproduction and blood pressure, demonstrating precedence for a critical contribution of astroglia to the regulation of key body processes. Recently, we discovered that genetically altering astroglial signalling in mice, increased food intake when the animals were given a palatable high-fat diet, supporting for the first time, a role these cells in a process that acutely regulates feeding. The overall purpose of this project is to follow up on this important finding, and to identify the mechanisms by which astroglia regulate food intake in response to a high-fat diet i.e. nutrient excess, and also to establish if similar mechanisms are involved in the feeding response to the opposite extreme, nutritional insufficiency e.g. fasting.

Our specific aims are:

1. To identify states of nutritional imbalance that cause astroglial activation in the hypothalamus.
2. To establish the role of astroglia in modulating the electrical activity of hypothalamic neurons that regulate feeding.
3. To determine how altering signalling in hypothalamic astroglia impacts food intake in response to in vivo nutritional imbalance.
4. To understand how manipulating astroglial signalling alters overall metabolism.

An improved understanding of the mechanisms by which food intake is regulated will benefit other scientists and clinicians working towards developing new therapies for disorders of food intake including obesity and anorexia.

Technical Summary

Obesity is a major public health crisis in the UK, but currently available pharmacological therapies are of limited/transient effectiveness. An improved understanding of the normal homeostatic regulation of food intake will inform development of new therapies for diseases characterised by dysregulated feeding such as obesity and anorexia-cachexia.

The most abundant cell type in the CNS, astroglia (AG) modify the "tone" of hypothalamic gonadotrophin-releasing hormone and magnocellular neurons to regulate reproduction and blood-pressure respectively. In contrast, little information is available on the role of AG in regulation of hypothalamic neural circuitry associated with the control of feeding. We recently discovered a novel role for AG in the homeostatic response to acute high-fat feeding in mice. Critically we discovered that preventing high-fat diet-induced AG activation in mice, by inhibiting the NFkappaB signalling pathway, increased food intake, supporting a physiological role for AG NFkappaB signalling in a homeostatic feedback loop that regulates feeding.

To follow up on this important finding, a vital next step is to define the mechanisms by which AG respond to systemic nutritional imbalance. Our central hypothesis is that AG are key metabolic sensors that contribute to the restoration of systemic energy homeostasis in the face of acute metabolic perturbations by modulating the firing activity of hypothalamic melanocortin neurons. We will address this hypothesis using the following specific aims:

1. To determine how AG activity is altered in response to acute changes in systemic energy availability in vivo.
2. To determine whether modulation of AG NFkappaB signalling alters the homeostatic response to acute changes in energy availability.
3. To determine the role of AG in neurophysiological modulation of hypothalamic neurons in response to acute changes in systemic nutrient availability.

Planned Impact

Economic: The studies proposed are addressing fundamental biological questions with importance for human health. While they are critical to address, in the short-term, there are unlikely to be any direct clinically relevant or commercially important findings. In the longer term, the data has potential to provide information that will be highly valuable for those looking for novel therapeutic targets for the treatment of disorders characterised by altered food intake, such as obesity and anorexia-cachexia. Obesity currently directly costs the NHS £4.2billion annually and there is a prevailing need for improved cost-effective therapies to reduce this economic burden. While surgical interventions are effective they are costly and there are a limited number of qualified surgeons available. Unfortunately, currently available pharmacological therapies for obesity are of limited and transient effectiveness. As such, studies like the ones proposed are critical, as before we can understand how to treat dysregulated feeding we need to improve our understanding of the normal physiological processes underlying the regulation of food intake.

Social: Obesity affects greater than 25% of the adult population in the UK. There is an information deficient amongst the general population with respect how to maintain a healthy body weight including what foods we should (or should not) consume, how much we should be eating and when, as well as how much physical activity we should be aiming for daily. An improved understanding how food intake is regulated normally could help individuals develop more effective strategies for weight-maintenance as well as weight-loss. For example, it takes approximately 30 minutes for the cue from the stomach to be relayed to the brain to communicate "fullness"/satiety. As such, this time-lag means that if you eat too fast your stomach may be full a long time before the message reaches your brain, resulting in overeating. Simple steps like slowing down the speed at which a meal is consumed enables time for effective communication between the stomach and the brain, which can reduce total food intake and lead to weight loss. This is an example of how improving our understanding of the normal physiological processes underlying the regulation of food intake could directly impact behaviour, leading to a positive social outcome. We will utilize social/public engagement forums such as "pint of science" to discuss the complexities of how the brain regulates food intake (including the outcomes of the proposed studies). This may promote behavioural changes with respect to how and what people eat, which in turn will have a prolonged impact on the health of the individuals and the wider community.
 
Description GW4 Medical Research Council Doctoral Training Programme
Amount £78,619 (GBP)
Organisation MRC Doctoral Training Program 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 10/2019
 
Description Small Project Grant
Amount £4,903 (GBP)
Organisation British Society for Neuroendocrinology 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2018
 
Description Brain Awareness Week - Public Presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Public presentation as part of the "Brain Awareness Week" activities at the University of Exeter. Open to all. Presented our latest research relating to understanding how the brain controls food intake and answered questions.
Year(s) Of Engagement Activity 2018
URL http://www.exeter.ac.uk/research/events/baw/
 
Description INSPIRE Taster day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Undergraduate students
Results and Impact I ran a 3 hour research taster day attended by three medical students (two from Exeter and one from Cardiff) to try and inspire them to get involved in research. I gave a 45 minute informal presentation about our ongoing research and then gave the students a tour of the labs and showed the some tissue sections down the microscope. The students then chatted to the PhD students in the lab about their research projects.
Year(s) Of Engagement Activity 2017
URL http://medicine.exeter.ac.uk/study/undergraduate/medicine/researchopportunities/inspireresearchtaste...
 
Description Invited Talk - Physiology of Obesity and Diabetes Symposium Aberdeen 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact An invited research presentation on the role of hindbrain astrocytes in regulating feeding behaviour at the a satellite symposium from the main annual Physiological Society meeting. The symposium was focused on the physiology of obesity and diabetes.
Year(s) Of Engagement Activity 2019
URL https://www.physoc.org/events/physiology-obesity-diabetes/
 
Description Invited plenary speaker - ESR event for British Society for Neuroendocrinology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A plenary presentation on astrocytes and the regulation of energy homeostasis at the British Society for Neuroendocrinology Early Career Symposium in Glasgow in December 2019. This event was attended by early career members of the society as week and more senior members. There were about 60 people in attendance.
Year(s) Of Engagement Activity 2019
URL https://www.neuroendo.org.uk/page.php?item_name=EVENT%3A+Neuroendo+Celebrate
 
Description Invited seminar speaker - Department of Neuroscience, Developmental and Cell Biology, University of Cambridge 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Delivered an invited seminar presentation at the department of Neuroscience, Development and Cell Biology at the University of Cambridge in January 2019 entitled "Astrocytes and the regulation of feeding behaviour".
Year(s) Of Engagement Activity 2019
 
Description Invited seminar speaker - Department of Pharmacology, University of Bath 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Delivered an invited seminar presentation at the department of Pharmacology at the University of Bath in October 2018 entitled "Astrocytes and the regulation of feeding behaviour".
Year(s) Of Engagement Activity 2018
 
Description Invited seminar talk - Department of Neuroscience, King's College London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Delivered an invited seminar presentation at the department of Neuroscience King's College London January 2018 entitled "The emerging role of astrocytes in the regulation of energy homeostasis".
Year(s) Of Engagement Activity 2018
 
Description Invited symposium presentation at 2018 Annual Meeting of American Diabetes Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Delivered an invited symposium presentation at 2018 annual meeting of the American Diabetes Association held in Orlando Florida June 2018 entitled "Astrocyte inflammation and energy homeostasis". The talk was open to all conference attendees including scientists from academia and industry, physicians, patients and patient groups. Estimated attendance was 80-100 people.
Year(s) Of Engagement Activity 2018
URL https://professional.diabetes.org/sites/professional.diabetes.org/files/media/final_program_pdf.pdf
 
Description Invited symposium presentation at 2018 International Congress in Neuroendocrinology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Delivered an invited symposium presentation at 2018 International Congress in Neuroendocrinology held in Toronta, Canada July 2018 entitled "Astrocyte inflammation and energy homeostasis". The talk was open to all conference attendees including scientists from academia and industry, and students. Estimated attendance was 80-100 people.
Year(s) Of Engagement Activity 2018
URL http://www.icn2018.org/scientific-program/symposia-theme-sessions/metabolism/#Symposium%20Role%20of%...
 
Description Pint of Science presentation - Talk to public 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I participated in the Exeter "Pint of Science" festival in 2016 and 2018. This involved giving a talk to the general public (approximately 30 people) in a pub about our research entitled "Are you hungry: Understanding how the brain controls food intake". After the presentation I answered questions. Tickets were sold and the event was sold out.
Year(s) Of Engagement Activity 2016,2018
URL https://pintofscience.co.uk/events/exeter/
 
Description Request for commennt - Science news for students website 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact I was asked by an American journalist to comment on a recent research study on how modulating hypothalamic inflammation in astrocytes (the topic of my MRC grant) can impact obesity development. I was interviewed by telephone by the journalist from the website "Science news for students" and asked to explain a comment on a recently published article by another scientist. The article was published online https://www.sciencenewsforstudents.org/article/brains-immune-system-can-play-role-weight-gain
Year(s) Of Engagement Activity 2017
URL https://www.sciencenewsforstudents.org/article/brains-immune-system-can-play-role-weight-gain