2. Academic Validation
  3. Adipocyte-specific Mlkl knockout mitigates obesity-induced metabolic dysfunction by enhancing mitochondrial functions

Adipocyte-specific Mlkl knockout mitigates obesity-induced metabolic dysfunction by enhancing mitochondrial functions

  • Cell Death Dis. 2025 Oct 6;16(1):683. doi: 10.1038/s41419-025-08004-1.
Juliette Tokgozoglu # 1 2,  Valeria Pistorio # 1 2 3,  Mirko Minini 1 2,  Pierre-Antoine Soret 1 2 4,  Virginie Steunou 1 2,  Jean-Louis Delaunay 1 2,  Julien Castel 5,  Serge Luquet 5,  Ivan Nemazanyy 6,  Carine Beaupère 1 2,  Laetitia Dinard 1,  Tatiana Ledent 1,  Aurore L'honoré 7,  Sara Lemoinne 1 2 8,  Chantal Housset 1 2 8,  Philippe Lesnik 2 3,  Vlad Ratziu 2 9,  Bruno Fève 1 2 10,  Tounsia Aït-Slimane 1 2 8,  Axelle Cadoret 1 2 8,  Nicolas Chignard 1 2 8,  Jérémie Gautheron 11 12 13
Affiliations

Affiliations

  • 1 Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012, Paris, France.
  • 2 Foundation for Innovation in Cardiometabolism And Nutrition, IHU-ICAN, F-75013, Paris, France.
  • 3 Sorbonne Université, INSERM, UMR_S1166, F-75013, Paris, France.
  • 4 Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, European Reference Network on Hepatological Diseases (ERN Rare-Liver), Saint-Antoine Hospital, Assistance Publique - Hôpitaux de Paris; Sorbonne University, INSERM, Saint-Antoine Research Center (CRSA), Paris, France.
  • 5 Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, Paris, F-75013, France.
  • 6 Paris Cité Université, INSERM, Structure Fédérative de Recherche Necker, Platform for Metabolic Analyses, F-75015, Paris, France.
  • 7 Sorbonne Université, INSERM, Institut de Biologie Paris Seine, IBPS, F-75005, Paris, France.
  • 8 Fédération Hospitalo-Universitaire (FHU), Gut, Liver & Microbiome Research (GLIMMER), F-75012, Paris, France.
  • 9 Sorbonne Université, INSERM, Centre de Recherche des Cordeliers, F-75006, Paris, France.
  • 10 Assistance Publique-Hôpitaux de Paris, AP-HP, Hôpital Saint-Antoine, Service Endocrinologie, F-75012, Paris, France.
  • 11 Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, F-75012, Paris, France. jeremie.gautheron@inserm.fr.
  • 12 Foundation for Innovation in Cardiometabolism And Nutrition, IHU-ICAN, F-75013, Paris, France. jeremie.gautheron@inserm.fr.
  • 13 Fédération Hospitalo-Universitaire (FHU), Gut, Liver & Microbiome Research (GLIMMER), F-75012, Paris, France. jeremie.gautheron@inserm.fr.
  • # Contributed equally.
PMID: 41053093 DOI: 10.1038/s41419-025-08004-1
Abstract

Obesity is a global epidemic characterized by chronic low-grade inflammation and metabolic dysfunction, with adipose tissue playing a pivotal role in these processes. The Mixed Lineage Kinase domain-like pseudokinase (MLKL) is a critical mediator of Necroptosis but also exhibits noncanonical roles in metabolic regulation. This study aimed to investigate the adipocyte-specific functions of MLKL in obesity. Using adipocyte-specific Mlkl knockout (MlklAdi-KO) mice, we observed reduced susceptibility to high-fat diet (HFD)-induced obesity, enhanced glucose tolerance, and improved Insulin sensitivity. MlklAdi-KO mice showed elevated energy expenditure independent of changes in food intake or locomotor activity, correlating with increased mitochondrial function and reduced lipid accumulation in white adipose tissue (WAT). Transcriptomic analyses of WAT revealed significant modulation of pathways linked to Oxidative Phosphorylation, inflammation, and lipid metabolism. Furthermore, metabolomic profiling highlighted reductions in TCA cycle intermediates, acylcarnitines, and pro-inflammatory Amino acids in MlklAdi-KO mice under HFD conditions. These findings were accompanied by improved hepatic lipid profiles and decreased steatosis, underscoring systemic benefits of adipocyte-specific Mlkl deletion. Mechanistically, Mlkl deficiency altered adipocyte differentiation. These results position MLKL as a promising therapeutic target for obesity and related metabolic disorders, emphasizing the need for future studies using conditional knockout and overexpression models to explore its cell-specific and noncanonical functions in metabolic regulation.

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