Amino acid sensing by hypothalamic tanycytes

Nearly two thirds of the UK population is overweight or obese. This excess weight elevates the risk of premature death and a range of illnesses, such as diabetes and stroke, which greatly reduce quality of life. The hypothalamus at the base of the brain controls body weight by regulating food intake (though feelings of hunger and satiety), and also deposition of fat and expenditure of energy (as heat production and activity). Understanding how the brain signals hunger and satiety is one way in which we can start to develop strategies to reduce the incidence of excess weight in the population.

The amino acid content of food is a powerful determinant of satiety. When plasma levels of amino acids are high, then so is the feeling of satiety. Amino acids are detected in the brain. So far four different brain regions have been described in which nerve cells respond to variations in the concentrations of amino acids. We propose to examine a 5th mechanism, which is unique as it is not mediated by nerve cells, but rather by specialized glial cells in the hypothalamus called tanycytes. We have already shown that tanycytes respond to amino acids, and that this may be via the activation of a receptor that also occurs in the taste buds of the tongue which is tuned to the "umami flavour" -the taste of L-amino acids. The overall purpose of this project is to understand why tanycytes sense amino acids in the brain and what this information is used for.

Our specific aims are to:
1. Characterize the mechanisms by which tanycytes detect and signal amino acid concentration;
2. Determine whether amino acid sensing via tanycytes interacts with other modalities of nutrient sensing in these cells -specifically their ability to sense glucose;
3. Test whether the properties of amino acid sensing via tanycytes can be altered by diet (fasting, amount of amino acids in food);
4. Examine the contribution of amino acid sensing via tanycytes to determination of food preferences, the amount of food intake, and ultimately control of body weight.

Understanding the mechanisms and functional roles of this new amino acid sensing pathway has many benefits for clinicians and related health professionals; commercial organizations; relevant medical charities; government agencies; and the public. Commercial companies may use our work to develop new types of food additive that reduce appetite, or to reformulate food so that it promotes feelings of satiety. In the light of our work, clinicians, dieticians, and relevant medical charities, may be able to modify advice on diet and eating patterns to various classes of patient to promote healthy eating and weight loss. Government agencies may be able to revise their policies with respect to the food industry and advice to the public to promote healthy eating.

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.

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.