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Afadin is a scaffold protein repressing insulin action via HDAC6 in adipose tissue.
Lundh, Morten; Petersen, Patricia Ss; Isidor, Marie S; Kazoka-Sørensen, Dolly Nm; Plucinska, Kaja; Shamsi, Farnaz; Ørskov, Cathrine; Tozzi, Marco; Brown, Erin L; Andersen, Emil; Ma, Tao; Müller, Ulrich; Barrès, Romain; Kristiansen, Viggo B; Gerhart-Hines, Zachary; Tseng, Yu-Hua; Emanuelli, Brice.
Afiliación
  • Lundh M; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Petersen PS; Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
  • Isidor MS; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Kazoka-Sørensen DN; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Plucinska K; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Shamsi F; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Ørskov C; Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
  • Tozzi M; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Brown EL; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Andersen E; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Ma T; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Müller U; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Barrès R; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Kristiansen VB; Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA, USA.
  • Gerhart-Hines Z; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • Tseng YH; Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark.
  • Emanuelli B; Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
EMBO Rep ; 20(8): e48216, 2019 08.
Article en En | MEDLINE | ID: mdl-31264358
Insulin orchestrates metabolic homeostasis through a complex signaling network for which the precise mechanisms controlling its fine-tuning are not completely understood. Here, we report that Afadin, a scaffold protein, is phosphorylated on S1795 (S1718 in humans) in response to insulin in adipocytes, and this phosphorylation is impaired with obesity and insulin resistance. In turn, loss of Afadin enhances the response to insulin in adipose tissues via upregulation of the insulin receptor protein levels. This happens in a cell-autonomous and phosphorylation-dependent manner. Insulin-stimulated Afadin-S1795 phosphorylation modulates Afadin binding with interaction partners in adipocytes, among which HDAC6 preferentially interacts with phosphorylated Afadin and acts as a key intermediate to suppress insulin receptor protein levels. Adipose tissue-specific Afadin depletion protects against insulin resistance and improves glucose homeostasis in diet-induced obese mice, independently of adiposity. Altogether, we uncover a novel insulin-induced cellular feedback mechanism governed by the interaction of Afadin with HDAC6 to negatively control insulin action in adipocytes, which may offer new strategies to alleviate insulin resistance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor de Insulina / Antígenos CD / Procesamiento Proteico-Postraduccional / Tejido Adiposo / Histona Desacetilasa 6 / Insulina / Proteínas de Microfilamentos / Obesidad Tipo de estudio: Etiology_studies Límite: Animals / Humans / Male Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2019 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptor de Insulina / Antígenos CD / Procesamiento Proteico-Postraduccional / Tejido Adiposo / Histona Desacetilasa 6 / Insulina / Proteínas de Microfilamentos / Obesidad Tipo de estudio: Etiology_studies Límite: Animals / Humans / Male Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2019 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido