OBJECTIVE: GDF11 is a member of the TGF-β superfamily that was recently implicated as potential "rejuvenating" factor, which can ameliorate metabolic disorders. The main objective of the presented study was to closely characterize the role of GDF11 signaling in the glucose homeostasis and in the differentiation of white adipose tissue. METHODS: We performed microscopy imaging, biochemical and transcriptomic analyses of adipose tissues of 9 weeks old ob/ob mice and murine and human pre-adipocyte cell lines. RESULTS: Our in vivo experiments employing GDF11 treatment in ob/ob mice showed improved glucose/insulin homeostasis, decreased weight gain and white adipocyte size. Furthermore, GDF11 treatment inhibited adipogenesis in pre-adipocytes by ALK5-SMAD2/3 activation in cooperation with the WNT/β-catenin pathway, whose inhibition resulted in adipogenic differentiation. Lastly, we observed significantly elevated levels of the adipokine hormone adiponectin and increased glucose uptake by mature adipocytes upon GDF11 exposure. CONCLUSION: We show evidence that link GDF11 to adipogenic differentiation, glucose, and insulin homeostasis, which are pointing towards potential beneficial effects of GDF11-based "anti-obesity" therapy.

Anatomy and Physiopathology Division Department of Clinical and Experimental Sciences University of Brescia Brescia Italy

CEITEC Central European Institute of Technology Masaryk University Brno Czech Republic

Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición Madrid Spain

Departament de Bioquímica i Biomedicina Molecular and Institut de Biomedicina Universitat de Barcelona Barcelona Spain

Department of Anatomy and Cell Biology Research Institute of the Medical University Varna Bulgaria

Department of Biomedical and Biotechnological Sciences Human Anatomy and Histology Section School of Medicine University of Catania Catania Italy

Department of Translational Stem Cell Biology Research Institute of the Medical University Varna Bulgaria

Division of Pediatric Endocrinology and Diabetes Department of Pediatrics and Adolescent Medicine University of Ulm Ulm Germany

Faculty of Medicine Department of Pathological Physiology Masaryk University Brno Czech Republic

Institut de Recerca Hospital Sant Joan de Déu Barcelona Spain

Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs University of Brescia Brescia Italy

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

National Center for Biomolecular Research Masaryk University Brno Czech Republic

Psychogenics Inc Tarrytown New York USA

Research Center for Toxic Compounds in the Environment Masaryk University Brno Czech Republic

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