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Novel biological and therapeutic mechanisms to enhance brown adipocyte formation and function

English title Novel biological and therapeutic mechanisms to enhance brown adipocyte formation and function
Applicant Stoffel Markus
Number 154460
Funding scheme Sinergia
Research institution Molekulare Gesundheitswissenschaften Departement Biologie ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Molecular Biology
Start/End 01.02.2015 - 31.01.2018
Approved amount 1'329'025.00
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All Disciplines (2)

Discipline
Molecular Biology
Physiology : other topics

Keywords (7)

brown adipose tissue; organic protein synthesis; cell surface signalling; miRNA; ANP; KAKA ligation; white adipose tissue

Lay Summary (German)

Lead
Braunes Fettgewebe zeichnet sich durch seine Fähigkeit aus gespeicherte Energie in Form von Fett in Wärme umzuwandeln. Beim Menschen wird die Aktivität der braunen Fettzellen durch Kältereize ausgelöst und durch das sympathische Nervensystem stimuliert. Neueste Erkenntnisse zeigen dass braunes Fett wesentlich zur Energieverbrennung im Körper beiträgt. Dieses Forschungsprojekt untersucht wie die Aktivität und Bildung von braunem Fett reguliert wird und ob es pharmakologisch beeinflusst werden kann.
Lay summary

Braunes Fettgewebe hat in den letzten Jahren den Fokus der Aufmerksamkeit als ein vielversprechendes neues Gewebe zum Targeting von Stoffwechselstörungen gewonnen. Bahnbrechende Erkenntnissen, dass erwachsene Menschen erhebliche Depots von braunem Fettgewebe besitzen können, und die Aktivierung dieses Gewebes zu einem erhöhten Energieaufwand und damit einhergehenden Gewichtsverlust führen kann, haben den Forschungsfokus auf Fragestellungen, wie  braunes Fettgewebe gebildet und aktiviert wird, verschoben.
Wir haben ein interdisziplinäres Konsortium gegründet, um zu ergründen wie  braune Fettzellen aus Vorläuferzellen gebildet werden und wie bereits differenzierte braune Fettzellen aktiviert werden können. Wir werden einen dreifachen Ansatz wählen, um Mechanismen, die diese Prozesse regulieren, zu identifizieren, und die Entwicklung neuartiger therapeutischer Ansätze, braune Fettzellen gezielt zu aktivieren, zu ermöglichen. 
Das erste Teilprojekt wird die Regulierung der braunen Fettzell-Aktivierung durch miRNAs untersuchen. Hierzu haben wir einige  interessante Kandidaten identifiziert, die hinsichtlich genregulatorischer Effekte in vitro  und in vivo funktional untersucht werden. Das zweite Projekt wird die Rolle von zirkulierende Proteinen und Zelloberflächenrezeptoren, die die Bildung und Funktion von braunen Fettgewebe beeinflnussen können, untersuchen. Letztlich werden wir einen interdisziplinären Ansatz verwenden, um funktionalisierte Proteine ??zu erzeugen, um ihre Rolle im braunen Fettzellstoffwechsel zu untersuchen. Dieses Teilprojekt wird funktionalisierte chimären Proteine ??aus verschiedenen Peptiden und Protein-miRNA-Konjugaten herstellen und auf ihre Wirksamkeit, Fettgewebe in vitro und in vivo zu beeinflussen, hin untersuchen.

Direct link to Lay Summary Last update: 22.05.2015

Lay Summary (English)

Lead
The primary function of brown fat is to generate body heat in newborns and protect them from hypothermia. Recent evidence suggests that brown fat is still present in adults and may contribute to energy expenditure and counteract obesity. This study aims to elucidate mechanisms of brown adipocyte formation and activation and to generate and test functionalized chimeric proteins from different peptides and protein-miRNA conjugates that will be evaluated for their efficacy to target specifically adipose tissue in vitro and in vivo.
Lay summary

Brown adipose tissue has gained the focus of attention in recent years as a promising new tissue for targeting metabolic disorders. After the seminal findings that adult humans have significant depots of brown adipose tissue and that activation of this tissue leads not only to increased energy expenditure and concomitant weight loss but also to the rapid and effective clearance of circulating metabolites such as triglycerides, free fatty acids and glucose multiple studies have focused on understanding how brown adipose tissue is formed.

We have formed and interdisciplinary consortium that will focus on three aspects leading to brown adipocyte activation, namely brown adipocyte formation from a cell precursor, brown/brite adipocyte formation from white to brown trans-differentiation and mature brown adipocyte activation. We will follow a three-pronged approach to identify mechanisms that regulate these processes and develop novel therapeutic approaches and compounds that can be used to target brown adipocytes specifically.

The first subproject will deal with the regulation of brown adipocyte activation and formation by miRNAs. We have identified several interesting candidates that show regulatory effects in vitro, which will be studied with regards to target gene engagement and in vivo functionality. The second project will focus on circulating proteins and cell surface receptors that can influence brown adipose tissue formation and function. We will use an interdisciplinary approach to generate functionalized proteins to study their role in brown fat cell metabolism. The last project of this proposal aims at generating functionalized chimeric proteins from different peptides and protein-miRNA conjugates that will be evaluated for their efficacy to target specifically adipose tissue in vitro and in vivo.

Direct link to Lay Summary Last update: 22.05.2015

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
James Petersson, University of Pennsylvania United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Barbara Cannon, Karolinska Sweden (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Stephan Herzig, DKFZ Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Keystone Symposium Talk given at a conference Role of miRNAs in diabetes 26.10.2015 Kyoto, Japan Stoffel Markus;
09.06. Keystone Smposium, MicroRNAs and Noncoding RNAs in Cancer, Keystone CO, U.S.A. Talk given at a conference Role of miRNAs in metabolism 09.06.2015 Keystone CO, United States of America Stoffel Markus;
50. Jahrestagung der Deutschen Diabetes Gesellschaft: Cross-Talk Type 2 Diabetes: Wissenschaft trifft Praxis, Berlin, Germany Talk given at a conference ‘Die Rolle der mikroRNAs in der Stoffwechselregulation’. 13.05.2015 Berlin, Germany Stoffel Markus;


Self-organised

Title Date Place
NCCR RNA & Disease Summer School in Saas-Fee 24.08.2015 Saas Fee, Switzerland

Awards

Title Year
Elected Vice President: European Association for the Study of Diabetes (EASD) 2015

Associated projects

Number Title Start Funding scheme
162887 Analysis of brite adipocyte formation and function 01.01.2016 Project funding (Div. I-III)

Abstract

Brown adipose tissue has gained the focus of attention in recent years as a promising new tissue for targeting metabolic disorders. After the seminal findings that adult humans have significant depots of brown adipose tissue and that activation of this tissue leads not only to increased energy expenditure and concomitant weight loss but also to the rapid and effective clearance of circulating metabolites such as triglycerides, free fatty acids and glucose multiple studies have focused on understanding how brown adipose tissue is formed.We have formed an interdisciplinary consortium that will focus on three aspects leading to brown adipocyte activation, namely brown adipocyte formation from a cell precursor, brown/brite adipocyte formation from white to brown trans-differentiation and mature brown adipocyte activation. We will follow a three-pronged approach to identify mechanisms that regulate these processes and develop novel therapeutic approaches and compounds that can be used to target brown adipocytes specifically. The first subproject will deal with the regulation of brown adipocyte activation and formation by miRNAs. We have identified several interesting candidates that show regulatory effects in vitro which will be studied with regards to target gene engagement and in vivo functionality. The second project will focus on circulating proteins and cell surface receptors that can influence brown adipose tissue formation and function. We will use an interdisciplinary approach to generate functionalized proteins to study their role in brown fat cell metabolism. The last project of this proposal aims at generating functionalized chimeric proteins from different peptides and protein-miRNA conjugates that will be evaluated for their efficacy to target specifically adipose tissue in vitro and in vivo. Taken together our studies will likely shed light on novel pathways that are important for brown fat formation and activation but will also provide a basis for much needed novel approaches to target this tissue for the treatment of obesity and associated co-morbidities.
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