Amino acid sensing by hypothalamic tanycytes
Lead Research Organisation:
University of Nottingham
Department Name: School of Life Sciences
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The UK faces a major challenge in combatting the high incidence of excess weight in the population. The diseases and pathologies which accompany excess body weight are likely to impact on the delivery and resourcing of healthcare for many years to come. Therefore biologically-informed strategies to intervene and reduce weight gain are vital for a healthy population. Amino acids are powerful suppressors of appetite and are detected in the brain. Nevertheless, the central sensing mechanisms involved in amino acid sensing are only incompletely understood. So far work has concentrated on neuronal mechanisms of amino acid sensing. We have discovered that specialized glial cells in the hypothalamus known as tanycytes sense circulating nutrients in the brain. We have previously shown that these cells use the sweet taste receptor (Tas1R), originally described in tongue to detect glucose. We have now found that tanycytes also respond to L-amino acids, possibly via the umami receptor that is part of the same Tas1R gene family as the sweet taste receptor.
Our objectives are to:
1. Define the signal transduction pathway for tanycyte amino acid sensing;
2. Analyze the relationship between glucose sensing and amino acid sensing in tanycytes;
3. Test whether the properties of amino acid sensing by tanycytes are diet-sensitive;
4. Establish the contribution of amino acid sensing via the umami receptor to food preference and energy homeostasis.
We shall use Ca2+ imaging to study tanycyte amino acid-sensing mechanisms in brain slices. We shall alter expression of the Tas1R1 subunit (an essential subunit of the umami receptor) to compare tanycyte amino acid responses in wild type mice, Tas1R1-null mice, and mice that express Tas1R1 only in tanycytes. By systematically altering the amino acid content of the diet and examining these three strains of mice we shall determine the behavioural roles of tanycytes in determining food preference, appetite and body weight.
Our objectives are to:
1. Define the signal transduction pathway for tanycyte amino acid sensing;
2. Analyze the relationship between glucose sensing and amino acid sensing in tanycytes;
3. Test whether the properties of amino acid sensing by tanycytes are diet-sensitive;
4. Establish the contribution of amino acid sensing via the umami receptor to food preference and energy homeostasis.
We shall use Ca2+ imaging to study tanycyte amino acid-sensing mechanisms in brain slices. We shall alter expression of the Tas1R1 subunit (an essential subunit of the umami receptor) to compare tanycyte amino acid responses in wild type mice, Tas1R1-null mice, and mice that express Tas1R1 only in tanycytes. By systematically altering the amino acid content of the diet and examining these three strains of mice we shall determine the behavioural roles of tanycytes in determining food preference, appetite and body weight.
Planned Impact
Who will benefit from this research
Academic:
Cross-disciplinary interactions with neural stem cell researchers, and taste sense researchers
Commercial:
Pharmaceutical companies and food-related research/pharma companies e.g. Ajinomoto Inc, Japan.
Commercial representative bodies such as the Food and Drinks Federation.
Government, Public Sector:
Food Standards Authority (FSA), NHS, Department of Health
3rd Sector:
Charities related to research and treatment of diseases exacerbated by excessive weight gain such as: the British Obesity Society; the British Heart Foundation; and Diabetes UK.
Professional bodies:
British Dietetic Association
Members of the Public
How will they benefit from the research
Academic:
Hypothalamic tanycytes are neural stem cells that are retained postnatally into the adult. Our work may suggest new ways that stem cells integrate information from their biological environment and how this determines whether they remain quiescent or divide and proliferate.
Taste receptors have been traditionally studied in the periphery. Our work shows that they play important roles in the brain.
Commercial:
Development of novel food additives or pharmacological interventions to target tanycyte amino acid sensing. Tailoring of additives to target particular pathways of central amino acid sensing, including development of novel non-tasting additives that cross the blood brain barrier and become modified to gain activity at umami receptor, to enhance feelings of satiety.
The Food and Drink Federation has a "Public Health Responsibility Deal". This includes reformulation of foods to reduce caloric values and development of new lower calorie options. This research may suggest new ways of meeting this public responsibility.
Government:
The FSA has responsibility for regulating novel foods, food additives, nutrition and health claims of food manufacturers. Our work may help to inform policy developments and recommendations in this area.
Department of Health: "Public Health Responsibility Deal" -formulation of policies on food, and "food pledges".
The NHS provides advice on diet and healthy living -our work on amino acid sensing by tanycytes may lead to new insights on how to improve this advice.
3rd Sector:
Several charities provide advice to the public on healthy living and eating to reduce the risk of major illnesses such as diabetes or cardiovascular disease, or pathological conditions such as obesity. They also offer advice on how to cope with and mange these types of condition. Our work may enable refinement and improvement of this advice, such as reformulating meals to increase feelings of satiety, or identifying particular foods to avoid.
Professional Bodies:
The British Dietetics Association is the professional association of dieticians. As well as upholding standards for the profession it provides advice to dieticians and the public. Such advice encompasses healthy living as well as diets for babies, children, pregnant women and patients with a range of medical conditions. Our work may help to update and inform this advice, particularly with regard to food additives and supplements, weight loss plans and special diets related to medical conditions.
Public:
Our work will increase awareness of the importance of the brain in determining appetite, food intake, and fat storage and the possible role that amino acids in diet combined with detection in brain may play.
Academic:
Cross-disciplinary interactions with neural stem cell researchers, and taste sense researchers
Commercial:
Pharmaceutical companies and food-related research/pharma companies e.g. Ajinomoto Inc, Japan.
Commercial representative bodies such as the Food and Drinks Federation.
Government, Public Sector:
Food Standards Authority (FSA), NHS, Department of Health
3rd Sector:
Charities related to research and treatment of diseases exacerbated by excessive weight gain such as: the British Obesity Society; the British Heart Foundation; and Diabetes UK.
Professional bodies:
British Dietetic Association
Members of the Public
How will they benefit from the research
Academic:
Hypothalamic tanycytes are neural stem cells that are retained postnatally into the adult. Our work may suggest new ways that stem cells integrate information from their biological environment and how this determines whether they remain quiescent or divide and proliferate.
Taste receptors have been traditionally studied in the periphery. Our work shows that they play important roles in the brain.
Commercial:
Development of novel food additives or pharmacological interventions to target tanycyte amino acid sensing. Tailoring of additives to target particular pathways of central amino acid sensing, including development of novel non-tasting additives that cross the blood brain barrier and become modified to gain activity at umami receptor, to enhance feelings of satiety.
The Food and Drink Federation has a "Public Health Responsibility Deal". This includes reformulation of foods to reduce caloric values and development of new lower calorie options. This research may suggest new ways of meeting this public responsibility.
Government:
The FSA has responsibility for regulating novel foods, food additives, nutrition and health claims of food manufacturers. Our work may help to inform policy developments and recommendations in this area.
Department of Health: "Public Health Responsibility Deal" -formulation of policies on food, and "food pledges".
The NHS provides advice on diet and healthy living -our work on amino acid sensing by tanycytes may lead to new insights on how to improve this advice.
3rd Sector:
Several charities provide advice to the public on healthy living and eating to reduce the risk of major illnesses such as diabetes or cardiovascular disease, or pathological conditions such as obesity. They also offer advice on how to cope with and mange these types of condition. Our work may enable refinement and improvement of this advice, such as reformulating meals to increase feelings of satiety, or identifying particular foods to avoid.
Professional Bodies:
The British Dietetics Association is the professional association of dieticians. As well as upholding standards for the profession it provides advice to dieticians and the public. Such advice encompasses healthy living as well as diets for babies, children, pregnant women and patients with a range of medical conditions. Our work may help to update and inform this advice, particularly with regard to food additives and supplements, weight loss plans and special diets related to medical conditions.
Public:
Our work will increase awareness of the importance of the brain in determining appetite, food intake, and fat storage and the possible role that amino acids in diet combined with detection in brain may play.
Organisations
People |
ORCID iD |
Fran Ebling (Principal Investigator) |
Publications
Bao R
(2019)
Genome sequencing and transcriptome analyses of the Siberian hamster hypothalamus identify mechanisms for seasonal energy balance.
in Proceedings of the National Academy of Sciences of the United States of America
Ebling F
(2018)
Tanycytes and hypothalamic control of energy metabolism
in Glia
Lewis J
(2020)
Whole-body and adipose tissue-specific mechanisms underlying the metabolic effects of fibroblast growth factor 21 in the Siberian hamster
in Molecular Metabolism
Lewis JE
(2017)
Antibody-Mediated Targeting of the FGFR1c Isoform Increases Glucose Uptake in White and Brown Adipose Tissue in Male Mice.
in Endocrinology
Lewis JE
(2017)
Reduced adiposity attenuates FGF21 mediated metabolic improvements in the Siberian hamster.
in Scientific reports
Lewis JE
(2017)
Tanycytes As Regulators of Seasonal Cycles in Neuroendocrine Function.
in Frontiers in neurology
Samms RJ
(2017)
FGF21 Is an Insulin-Dependent Postprandial Hormone in Adult Humans.
in The Journal of clinical endocrinology and metabolism
Samms RJ
(2015)
Antibody-Mediated Inhibition of the FGFR1c Isoform Induces a Catabolic Lean State in Siberian Hamsters.
in Current biology : CB
Travaglio M
(2019)
Role of hypothalamic tanycytes in nutrient sensing and energy balance.
in The Proceedings of the Nutrition Society
Description | Tanycytes are non-neuronal cells that line the wall of the third ventricle of the hypothalamus and contact the cerebrospinal fluid within the brain. They have been shown to detect glucose in cerebrospinal fluid, a process that likely contributes to control of appetite. Surprisingly, tanycytes in rodents also respond to non-nutritive sweeteners such as sucralose and Acesulfame-K. These compounds are known to be ligands of the sweet taste receptor normally found in the tongue, so tanycytes can sense glucose using taste sensors rather than classical glucose responsive mechanisms, for example those found in the pancreas that elicit insulin secretion. The overall aim of this grant was to determine whther tanycytes also detect amino acids as these are important nutrients that potentially also signal satiety, and to determine whether this process also uses taste receptors more commonly associated with the tongue. Both calcium imaging and biosensing of ATP were used to detect tanycyte responses to l-amino acids, and results were confirmed in genetically modified mice that lacked specific taste receptors. mice lacking the Tas1r1 gene, as well as an mGluR4 receptor antagonist. It was found that lysine, arginine and alanine were all detected specifically by tanycytes, but this is also using receptors previously implicated in taste cells, for example the umami receptor. Data obtained so far have been published in two manuscripts in academic journals: Lazutkaite et al (2017) Amino acid sensing in hypothalamic tanycytes via umami taste receptors. Molecular Metabolism. 2017 Nov;6(11):1480-1492. doi: 10.1016/j.molmet.2017.08.015 Benford et al (2017) A sweet taste receptor-dependent mechanism of glucosensing in hypothalamic tanycytes. Glia. 2017 May;65(5):773-789. doi: 10.1002/glia.23125 |
Exploitation Route | The long-term impact of this work is that it may be possible to manipulate amino acid composition of dietary componenets to promote satiety and reduce food intake, this would have clear benefits with regard to management of body weight an amelioration of associated morbidity. This long-term impact is unlikely to be realised until we understand how and where the brain senses specific amino acids. The studies funded by this grant provide further evidence that tanycytes in the hypothalamus are directly sensitive to specvific aino acids, so a likely detection region, but also indicate that the molecular mechanisms of sensing are more complex than we initially hypothesised. |
Sectors | Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology |
Description | BBC Radio 2 (8 October 2017) |
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 | Public/other audiences |
Results and Impact | Live interview on mainstream radio (Simon Mayo show, 8 October 2017), about sleep, and use of hamsters as an approach to understanding how we control appetite and body weight |
Year(s) Of Engagement Activity | 2017 |
Description | Brain Masterclass 1 February 2017 (Nottingham) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | I ran a workshop with approximately 35 Year 12 pupils from local/regional schools. The focus was on neuroscience and the brain, so the main activity was a visit to the dissecting room to view human brains and prosections, and to discuss how structure underlies function. The workshops are designed to inform school students about the relevance of neuroscience and provide an insight into higher education and research. I explained how research on tanycytes and on FGF21 funded by my current BBSRC grants provided new insights into how the brain senses our nutritional and metabolic staus and thereby regulates our appetite and body weight. |
Year(s) Of Engagement Activity | 2017 |
Description | Pint of Science 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Pint of Science is a national public engagement/science festival. I presented and ran a session on 'Chrononutrition' at a sold out event at Rough Trade in Nottingham on 21 May 2019. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.bna.org.uk/meetings/pint-of-science-2019-neuro-calendar/#east-midlands |
Description | Pint of Science Festival 23-25 May 2016 (Nottingham) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | Pint of Science is a series of public engagement events: "Real scientists in pubs near you". I participated in the Beuatiful Minds event at the Canal House in Nottingham, with an audience of over 100 members of the public. The evening comprised a series of talks and questions sessions interspersed with short activities, so I spoke about our research into obesity and the value of animal models. I presented examples from my current BBSRC-funded projects concerning nutrient sensing by tanycytes and by muscle, and the role of FGF21, and discussed how this research provides new insights into how we regulate our appetite and body weight. This led to a large number of personal discussions later in the evening with a wide range of different people. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.pintofscience.co.uk |