The necroptosis-inducing pseudokinase mixed lineage kinase domain-like regulates the adipogenic differentiation of pre-adipocytes

  • iScience. 2022 Sep 19;25(10):105166. doi: 10.1016/j.isci.2022.105166.
Julie Magusto  1  2 ,  Carine Beaupère  1  2 ,  Marta B Afonso  3 ,  Martine Auclair  1  2 ,  Jean-Louis Delaunay  1  2 ,  Pierre-Antoine Soret  1  2  4 ,  Gilles Courtois  5 ,  Tounsia Aït-Slimane  1  2 ,  Chantal Housset  1  2  4 ,  Isabelle Jéru  1  2  6 ,  Bruno Fève  1  2  7  8 ,  Vlad Ratziu  2  9  10 ,  Cecilia M P Rodrigues  3 ,  Jérémie Gautheron  1  2
Affiliations
  • 1. Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), 27 rue Chaligny, 75571 Paris Cedex 12, France.
  • 2. Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), Paris, France.
  • 3. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
  • 4. Assistance Publique-Hôpitaux de Paris (AP-HP), Saint-Antoine Hospital, Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CMR MIVB-H), Paris, France.
  • 5. Inserm, CEA, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Grenoble, France.
  • 6. AP-HP, Pitié-Salpêtrière Hospital, Department of Medical Genetics, Paris, France.
  • 7. AP-HP, Saint-Antoine Hospital, Department of Endocrinology, Paris, France.
  • 8. Centre National de Référence des Pathologies Rares de l'Insulino-Sécrétion et de l'Insulino-Sensibilité (PRISIS), Saint-Antoine Hospital, Paris, France.
  • 9. Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Hepatology, Paris, France.
  • 10. Sorbonne Université, Inserm, Centre de Recherche des Cordeliers (CRC), Paris, France.
PMID: 36204273 DOI: 10.1016/j.isci.2022.105166
Abstract

Receptor-interacting protein kinase-3 (RIPK3) and Mixed Lineage Kinase domain-like (MLKL) proteins are key regulators of Necroptosis, a highly pro-inflammatory mode of cell death, which has been involved in various human diseases. Necroptotic-independent functions of RIPK3 and MLKL also exist, notably in the adipose tissue but remain poorly defined. Using knock-out (KO) cell models, we investigated the role of RIPK3 and MLKL in adipocyte differentiation. Mlkl-KO abolished white adipocyte differentiation via a strong expression of Wnt10b, a ligand of the Wnt/β-catenin pathway, and a downregulation of genes involved in lipid metabolism. This effect was not recapitulated by the ablation of RIPK3. Conversely, Mlkl and RIPK3 deficiencies did not block beige adipocyte differentiation. These findings indicate that RIPK3 and MLKL have distinct roles in adipogenesis. The absence of MLKL blocks the differentiation of white, but not beige, adipocytes highlighting the therapeutic potential of MLKL inhibition in obesity.

Keywords
Biological sciences; Cell biology; Molecular biology; Stem cells research.
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