The role of wnt signalling network in adipose tissue development and plasticity

Lead Research Organisation: University of Cambridge
Department Name: Clinical Biochemistry

Abstract

Obesity and diabetes are becoming increasingly prevalent in the western world. Individuals that are obese and diabetic are at high risk of dying at an early age from heart attacks. Hence, obesity and the related metabolic diseases represent a significant public health issue. The ideal strategy would be to prevent individuals from becoming obese, but it is clear that current efforts have been ineffective at curbing this epidemic. By increasing our understanding of how normal fat tissue develops and adjusts its size in response to environmental changes, we may identify more effective strategies for maintaining their health despite increased body weight. We think that adipose tissue does not have an unlimited capacity to store fat and it is when this level is surpassed that clinical problems arise. Our research aims to identify and study a group of proteins (Wnts) that are related to tissue development and alter the program of fat cell formation. These proteins can act as messengers to control the size and recruitment of new fat tissue. How these proteins bring about these changes in human fat tissue remains unclear. We have shown that key Wnt signalling molecules are co-ordinately regulated in human fat cell formation. We have also identified a human mutation in one of these molecules, in an obese individual. This mutation appears to render the molecule signalling defective and may be related to their obesity. Herein, we propose to identify and characterise the full complement of these molecules and identify their roles in altering fat tissue size in specific experimental models of obesity and fat cell development. We will also generate a new model that will allow us to investigate the role of this novel wnt mutant in whole body energy storage. We hypothesise that the wnt signalling network orchestrates the balance between fat cell recruitment and size. Alterations in this network may result in increased fat tissue size and cell number that ultimately may have important metabolic consequences.

Technical Summary

A fundamental question in adipose tissue biology is the nature of the signals determining 'when' and 'how' preadipocytes differentiate. The Wnt signalling network is particularly suited to regulate this. Although, a few Wnts are implicated in murine adipogenesis, the involvement of the wnt network in human adipogenesis and tissue plasticity remains unclear. We have shown that key Wnt signalling molecules are co-ordinately regulated in human adipogenesis and facilitate differentiation. We have also identified a human wnt10b mutant, which is signalling defective and cannot maintain the preadipocyte phenotype. Herein, we propose to 1) identify differentially regulated wnt signals in an in vivo model of hypertrophic adipose tissue (PPAR gamme2-KO), 2) characterise their effects on adipogenesis and 3) generate a wnt10b loss of funcion mutant knock-in mouse. We hypothesise that the wnt signalling network orchestrates the balance between adipocyte maturation and preadipocyte recruitment. Alterations in this network may result in hyperplasic/hypertrophic adipose tissue with important metabolic consequences.

Publications

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Christodoulides C (2009) Adipogenesis and WNT signalling. in Trends in endocrinology and metabolism: TEM

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Sethi JK (2010) Wnt signalling and the control of cellular metabolism. in The Biochemical journal

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Vidal-Puig A (2013) Adipose tissue expandability, lipotoxicity and the metabolic syndrome in Endocrinología y Nutrición

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Vidal-Puig A (2013) Adipose tissue expandability, lipotoxicity and the metabolic syndrome. in Endocrinologia y nutricion : organo de la Sociedad Espanola de Endocrinologia y Nutricion

 
Description This grant raised the concept of adipose tissue expandability as an intellectual frameworkto understand teh link between obesity and metabolic complications. The wnt system is central to adipose tissue expandability.
Exploitation Route Adipose tissue expandability is a concept established and now being evaluated in human clinical research
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Organisation of conferences/Courses
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact It is expected these training schemes have contributed to better care and scientifc developments. Member of the Scientific Organising Committee 1. Cambridge, United Kingdom. 30th June - 2nd July 2015. EAS Advanced Course in Cardiometabolic Phenotyping in Rodents. 2. Boston, USA. 5th - 9th June 2015. ADA Scientific Sessions Insulin Action/Molecular Metabolism. 3. Colorado, USA. 9th - 13th February 2015. Keystone Symposia - Systems Biology of Lipid Metabolism. 4. Madrid, Spain. 7th - 8th November 2014. CNIC Conference "Energy homeostasis and metabolic disease". 5. Madrid, Spain. 7th-8th November 2014. Energy homeostasis and metabolic disease. CNIC. 6. Cambridge, UK. 30th September 2014. 14th Annual Cambridge Immunology Forum Meeting. • Member of the Scientific Organising Committee Keystone meeting on Nuclear receptors. (http://www.keystonesymposia.org/Meetings/viewMeetings.cfm?MeetingID=1235?Tab=travel) Austria (2013) • Member of the Scientific Organising Committee 15th European Congress of Endocrinology 27th April - 1st May 2013. Copenhagen, Denmark (http://www.ece2013.org/committees.aspx) • Director of The European Atherosclerosis Society Advanced Course IV: Murine Genetics and Cardiometabolic Phenotyping 11th - 14th July 2012. Cambridge, United Kingdom (http://www.eas-society.org/advanced-course-iv,-cambridge.aspx • Member of the Organising Scientific Committee of The Royal Society and Academy of Medical Sciences symposium on "Brown adipose tissue: a new human organ?" London (2012) (http://www.physoc.org/me2012) • Member of the Organising Scientific Committee The Obese Species Workshop Sicily, Italy. 21st - 26th October (2011) http://theobesespecies.unipr.it/. • Member of the Organising Scientific Committee for the meeting of the EAS in Hamburg. Germany (2010) • Member of the Organising Scientific Committee of the 49th International Conference on the Bioscience of Lipids. Maastrich (2008)
 
Title 3D Culture of Stem cells 
Description 3D tissue culture system to study cross talk between stem cells 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact Improvement in quality of results by better mimicking in vivo intercellular interactions. 
 
Title Citometry 
Description Development of Flow cytometry to study adipose tissue macrophages 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Improvement and refinement allowing decreasing the number of animals required 
 
Description Dusseldorf, Germany. 10th October 2017. Universitäts Klinikum Lecture Series - CRC1116 "master switches after myocardial infarction" 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Dusseldorf, Germany. 10th October 2017. Universitäts Klinikum Lecture Series - CRC1116 "master switches after myocardial infarction"
Year(s) Of Engagement Activity 2017
URL http://www.irtg1902.hhu.de/schedule/schedule-single-view.html?tx_cal_controller%5Bgetdate%5D=2017101...
 
Description Keystone Symposia on Diabetes/Obesity and Adipose Tissue Biology. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Keystone Conference Lecture. Colorado, USA. 22nd - 27th January 2017.
Year(s) Of Engagement Activity 2017
URL http://healthdocbox.com/amp/69735120-Diabetes/Diabetes-january-22-26-2017-keystone-conference-center...
 
Description Lisbon, Portugal. 11th-15th September 2017. 53rd EASD Annual Meeting. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Lisbon, Portugal. 11th-15th September 2017. 53rd EASD Annual Meeting. >150 attendants to symposium on Obesity associated metabolic complications.
Year(s) Of Engagement Activity 2017
URL https://d-net.idf.org/en/events/369-53rd-easd-annual-meeting-in-lisbon-portugal.html
 
Description Majorca, Spain. 16th October 2017. Seminar at Illes Balears Institute for Health Research. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Majorca, Spain. 16th October 2017. Seminar at Illes Balears Institute for Health Research. Research seminar. >80 attendees.
Year(s) Of Engagement Activity 2017
URL https://www.arabalears.cat/balears/Antonio-Vidal-Puig-nostres-estalviadors-lluitar_0_1892210855.html
 
Description Adipose tissue expandaqbility-EL COMERCIO ASTURIAS 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact <>
Antonio Vidal-Puig, catedrático en Cambridge y director adjunto del Centro de Obesidad y Enfermedades Asociadas. Premio Internacional Hipócrates 2015
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Year(s) Of Engagement Activity 2015
URL http://www.elcomercio.es/asturias/201511/27/puede-obeso-saludable-siempre-20151127002423-v.html
 
Description Blog 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Fighting fat with fat
Obesity is one of the most important biomedical problems in our society and also one of the most frustrating to tackle. For this reason, the recent identification of functional brown fat in adult humans has made the obesity research community very excited. Read more here.

Sanger Institute Blog by Dr Stefania Carobbio

Projection of our lab
Year(s) Of Engagement Activity 2014
URL http://www.tvp.mrl.ims.cam.ac.uk/events/
 
Description Cambridge Metabolic Network/Danish Diabetes Association Course for PhD Students. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Course sponsored by NOVO foundation from Denmark, 35 PhD students from Cambridge and Denmark.
Year(s) Of Engagement Activity 2017
URL https://www.danishdiabetesacademy.dk/events/lipid-metabolism-new-methods-and-translational-aspects
 
Description Cherry Hinton Lions Under 10s Blue Football Club sponsored by IMS/TVP lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact This is an action to promote fitness in children as a strategy to prevent orreverse obesity

Children know what is the IMS and that obesity and diabetes can be prevented by exercise.
Year(s) Of Engagement Activity 2014
URL http://www.tvp.mrl.ims.cam.ac.uk/events/
 
Description Harrogate, United Kingdom. 6th-8th November 2017. Society for Endocrinology BES Conference. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Harrogate, United Kingdom. 6th-8th November 2017. Society for Endocrinology BES Conference. Lecture related to Medal award.
Year(s) Of Engagement Activity 2017
URL https://www.endocrinology.org/events/sfe-bes-conference/sfe-bes-2017/
 
Description Lisbon, Portugal. 21st-23rd May 2017. Aegerion ECE Symposium. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Lisbon, Portugal. 21st-23rd May 2017. Aegerion ECE Symposium. This was a symposia with clear clinical translational implications addressed to practitioners that had implications on their practice.
Year(s) Of Engagement Activity 2017
URL http://www.ece2017.org/media/1123/ece-2017-satellite-programmes_280317.pdf
 
Description London, UK. 11th March 2015. Diabetes UK for the Adipose Plenary Conference. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The Diabetes UK Professional Conference, organized by the Diabetes UK will take place from 11th March to the 13th March 2015 at the Excel London in London, United Kingdom. The conference will cover areas like basic science, clinical science, education, clinical care management, healthcare delivery and psychological care.
Year(s) Of Engagement Activity 2015
URL http://10times.com/diabetes-uk-professional-conference
 
Description Members of the TVP lab recently attended the 1st ICAN conference series in Cardiometabolic Disease in Paris. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact TVP Lab members give presentations and posters at 1st ICAN conference series in Cardiometabolic Disease

Members of the TVP lab recently attended the 1st ICAN conference series in Cardiometabolic Disease in Paris. Vanessa Pellegrinelli was selected to give a presentation, and Camilla Ingvorsen, Guillaume Bidault, and Vivian Peirce were selected to present posters. Vivian Peirce was a joint-winner of Young Investigator poster award.



Projection of our lab
Year(s) Of Engagement Activity 2014
URL http://www.tvp.mrl.ims.cam.ac.uk/events/
 
Description Nanjing, China. 8th May 2017. Lecture at Nanjing Biomedical Research Institute. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact Nanjing, China. 8th May 2017. Lecture at Nanjing Biomedical Research Institute. Talk at this institute in China in front of > 100 students.
Year(s) Of Engagement Activity 2017
 
Description Royal Swedish Academy of Sciences, Journal of Internal Medicine - Key Symposium "Metabolic complications of obesity" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Organisation of symposia with 150 attendants, 28 speakers from EU, USA, JAPAN, CHINA. Top symposium supported by the Swedish Academy of Sciences and the Journal of Internal Medicine.
Year(s) Of Engagement Activity 2017
URL http://www.mrl.ims.cam.ac.uk/event/metabolic-complications-obesity/
 
Description Toulouse, France. 28th April 2017. Seminar at INSERM. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Toulouse, France. 28th April 2017. Seminar at INSERM. Dissemination of research outcomes to research commnity
Year(s) Of Engagement Activity 2017
URL https://www.stromalab.fr/actualites/pr-toni-vidal-puig-university-of-cambridge-uk/