title: Insulin resistance is associated with MCP1-mediated macrophage accumulation in skeletal muscle in mice and humans.
abstract: Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFα expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: David
authors.initials: D
authors.lastname: Patsouris
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Jingwei-Ji
authors.initials: JJ
authors.lastname: Cao
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Amelie
authors.initials: A
authors.lastname: Bravard
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France; Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Center for European Nutrition, Safety and Health, Pierre- Bénite, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Durand
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Durand
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Marie-Agnés
authors.initials: MA
authors.lastname: Chauvin
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Laugerette
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Debard
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France; Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Center for European Nutrition, Safety and Health, Pierre- Bénite, France.
authors.forename: Marie-Caroline
authors.initials: MC
authors.lastname: Michalski
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France; Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Center for European Nutrition, Safety and Health, Pierre- Bénite, France; Hospices civils de Lyon, Service de Nutrition et Diabétologie, Pierre- Bénite, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Laville
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France; Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Center for European Nutrition, Safety and Health, Pierre- Bénite, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.affiliation: Institut National de la santé et de la recherche médicale, Unité Mixte de Recherche 1060, Laboratoire CarMeN, Université Lyon 1, Faculté de Médecine Charles Merieux Lyon-Sud, Lyon, France; Centre de Recherche en Nutrition Humaine, Rhône-Alpes, Center for European Nutrition, Safety and Health, Pierre- Bénite, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000502:physiology*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009220:Myositis / Q000276:immunology* / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2