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URN: urn:nbn:de:bsz:25-opus-28121
URL: http://www.freidok.uni-freiburg.de/volltexte/2812/

Poli, Cecilia

Functional analysis of the transcriptional co-factor Fhl2 during adipocyte differentiation

Funktionelle Analyse des transkriptionellen Ko-Faktors FHL2 während der Fettzelldifferenzierung

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Kurzfassung in Englisch

The transcriptional co-factor Fhl2 (Four and a half LIM domains 2) belongs to a family of proteins consisting exclusively of LIM domains. Since the LIM motif mediates protein-protein contacts, the LIM-only proteins are thought to constitute platforms for the assembly of complexes. Accordingly, Fhl2 has diverse interaction partners in a variety of cellular contexts and is involved in the regulation of many functions such as signal transduction, cell proliferation, cell survival and transcription. The objective of this work was to further analyze the biological role of Fhl2 . The results presented here characterize Fhl2 as a novel modulator of adipogenesis in vitro and in vivo. Additionally, another set of results helped to reveal Fhl2 as a modulator of osteoblast function during bone formation.
Adipogenesis is a complex hierarchical differentiation process. Diverse stimuli promote preadipocyte maturation by induction of a transcriptional program that ultimately leads to expression of the so-called master regulators of adipocyte differentiation, PPAR>= and C/EBP±. These transcription factors in turn activate expression of genes involved in maintaining both the phenotype and function of mature adipocytes. Fhl2 is expressed in NIH/3T3-L1 preadipocytes and also in the stromal-vascular fraction of adipose tissue where preadipocytes are located. Upon induction of differentiation, Fhl2 is massively downregulated. Enforced expression of Fhl2 in 3T3-L1 preadipocytes leads to a dramatic decrease in the transcript levels of the master regulator C/EBP±, and of its target genes Adiponectin, Adipsin and Resistin. Accordingly, when triggering Fhl2-/- mouse embryonic fibroblasts (MEFs) to undergo adipogenesis, these same genes are upregulated at earlier time points in comparison to normal MEFs. In transient transfections, Fhl2 mediates repression of the C/EBP± promoter and chromatin immunoprecipitation analyses demonstrate that Fhl2 is directly recruited to the C/EBP± promoter. Taken together, the presented data establish Fhl2 as a modulator of a key adipogenic factor. In the Fhl2-/- animal model, the lack of Fhl2 results in resistance to high fat diet-induced obesity. Future analysis of the Fhl2 gene-deficient animals will contribute to uncover the signalling pathways that are important for the regulation of energy homeostasis. This work describes novel biological roles for Fhl2 in the regulation of adipogenesis and bone formation, raising the intriguing possibility that Fhl2 could be considered for therapeutic strategies to treat both obesity and osteoporosis, two major health problems in industrialized countries.

Kurzfassung in Sonst.

El co-factor transcripcional Fhl2 pertenece a una familia de proteinas que consisten exclusivamente de dominios LIM. Estas proteinas pueden comportarse como plataformas para el ensamblado de complejos multiproteicos ya que los dominios LIM median interacciones entre polipéptidos. De esta manera, Fhl2 interactúa con varias proteinas en diversos contextos celulares participando así en la regulación de muchas funciones como proliferación, transcripción y mantenimiento del citoesqueleto. El objetivo de este trabajo fue caracterizar la función biológica de Fhl2. Los resultados presentados aqui demuestran una nueva función de Fhl2 como modulador de la diferenciación de adipocitos in vitro e in vivo.

SWD-Schlagwörter: Genregulation , Zelldifferenzierung , Weiße Fettzelle
Freie Schlagwörter (deutsch): Fhl2, Adiponectin
Freie Schlagwörter (englisch): Fhl2, transcription, adipogenesis, Adipokines
MSC Klassifikation 92C40
Institut: Univ.-Frauenklinik
Fakultät: Fakultät für Biologie
DDC-Sachgruppe: Biowissenschaften, Biologie
Dokumentart: Dissertation
Erstgutachter: Schüle, Roland (Prof. Dr.)
Sprache: Englisch
Tag der mündlichen Prüfung: 19.12.2006
Erstellungsjahr: 2006
Publikationsdatum: 17.01.2007