Hypothalamic regulation of appetite by thyroid hormones

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Thyroid hormone is one of the most important mechanisms for controlling body function. The effects of a large excess or the absence of thyroid hormone is well known. However despite its importance of thyroid hormones their role in the day to day regulation of food intake is unknown. It is known that a large excess of T3 increases metabolic rate and this is thought to result in an indirect increase in appetite. However, recently we found that low doses of thyroid hormone increased food intake without affecting metabolic rate. This effect seemed to be mediated by part of the brain called the hypothalamus, specifically a region of the hypothalamus called the ventromedial nucleus (VMN). We now plan to establish the role of thyroid hormone in the VMN in the day to day regulation of food intake and energy expenditure. Recently mice which have been genetically altered to allow levels of thyroid hormone or thyroid hormone receptors to be reduced in specific regions of the brain have been produced. Using these mice we will establish the role of thyroid hormones in regulating food intake on a day to day basis and identify the receptor which mediates these effects. This work will allow us to establish the role and importance of thyroid hormone in regulating food intake.

Technical Summary

Whilst a great deal of information is known about the importance of thyroid hormones in development and their pharmacological effects, their physiological role is still unclear. Recently it has become evident that tissue levels of thyroid hormone are regulated by the balance of local enzymatic activation and inactivation rather than the plasma levels of the hormones. We have recently shown that tlow doses of thyroid hormone increase food intake without affecting metabolic rate; an effect that is mediated via the ventromedial nucleus (VMN) of the hypothalamus. The work in this grant is to establish the physiological role and importance of thyroid hormones in the VMN in regulating food intake. To achieve this we will utilise three newly developed strains of transgenic mice. The strains of transgenic mice are pROSA26D3 which has a floxed stop transcription cassette between the ROSA26 promoter and deiodinase-3 (D3), the enzyme responsible for inactivating thyroid hormone. These mice will be stereotaxically injected with recombinant adeno-associated virus expressing a Cre-GFP fusion (AAVCre-GFP) into the VMN. This will result in decreased levels of T3 within this nucleus and thus its physiological role in the regulation of food intake can be established. The other mice are TRaflox/flox and TRbflox/flox in which Cre recombinase sites have been inserted into either the thyroid receptor a or b genes which allows specific inactivation of these receptors using Cre. Mice which are homozygous either for TRaflox/flox or TRbflox/flox or bothTRaflox/flox and TRbflox/flox will be injected with AAVCre-GFP into the VMN to specifically delete the receptor(s) within this hypothalamic nucleus. This will allow the identity of the receptor through which T3 exerts its effects on food intake to be identified. Together the experiments in this proposal will establish the physiological role and importance of T3 in the regulation of food intake and the receptor through which it acts
 
Description The project was successful in all of its aims and objectives. Two different murine models were produced in which there was either deletion of the thyroid hormone receptor ß (TRß) or activation of type 3 deiodinase (D3) specifically in the hypothalamic VMN. This was achieved by stereotaxic injection of rAAV expressing a CRE/GFP fusion protein into the VMN of either TRßflox/flox or pRosa26/D3 flox-stop/flox-stop mice. In mice with specific VMN deletion of the TRß a marked phenotype of increased weight gain and food intake was observed, compared to controls. The weight gain in this model was of a similar magnitude to that seen in mice with targeted deletion of either POMC or the melanocortin 4 receptor. This striking phenotype was replicated in mice with with VMN specific over-expression of D3 and thus reduced thyroid hormone levels in the VMN. The increased weight gain was due to an increase in food intake and was not associated with any changes in energy expenditure. Similar results were also seen in rats in which D3 had been over-expressed in the VMN using rAAV. All of these changes occurred without alteration in systemic thyroid status, thus circulating levels of freeT4 freeT3 and TSH were unchanged in both the mouse and the rat models. Two manuscripts are currently being prepared presenting this data. One will be submitted to Nature Medicine; the other to FASEB journal. We expect several other papers and presentations to arise from this work. In addition we expect this work will be of great interest to the public and we will actively seek to maximise coverage of these findings in the media and with outreach activities. We will utilise the media offices at both Imperial College and the BBSRC to achieve this.
Exploitation Route The data provide a rationale for the development of pharmaceutical agents which target this system to regulate food intake and body weight.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology
 
Description The work is of immense interest to the pharmaceutical industry. We currently have been contact with several large pharmaceutical companies including Glaxo-Smith Klein and Astra-Zeneca with respect to this work and data. We are currently investigating the possibility of developing formal collaborations and research projects exploiting the models and data. The post doctoral scientist employed on the grant was recently head hunted by a medium sized biotechnology company, Prosidion. He was targeted for recruitment as a result of the experience gained whilst working on this project. One of the PhD students whose thesis was based on the work conducted as part of this project was half funded by Industrial sponsorship with departmental funding paying the remainder.
First Year Of Impact 2011
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic
 
Description clinician scientist 04-09
Amount £711,910 (GBP)
Organisation Department of Health Social Services and Public Safety (DHSSPS) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2004 
End 01/2009
 
Description clinician scientist 05-10
Amount £814,868 (GBP)
Organisation Department of Health Social Services and Public Safety (DHSSPS) 
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 02/2005 
End 01/2010
 
Description ctf 09-12
Amount £206,700 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2009 
End 10/2012
 
Description ctf 09-12
Amount £235,491 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 11/2009 
End 10/2012
 
Description equipment grant
Amount £35,000 (GBP)
Organisation Arthritis Research UK 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2008 
End 07/2009
 
Description fellowship 06-09
Amount £158,000 (GBP)
Organisation The Diabetes Research & Wellness Foundation (DRWF) 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 12/2006 
End 11/2009
 
Description scholarship
Amount £75,000 (GBP)
Organisation Sir Jules Thorn Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2008 
End 07/2011