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Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice
Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom; Institut du Thorax, Institut National de la Santé et de la Recherche Médicale U915, Nantes, France.
Department of Clinical Biochemistry, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
Technical Research Centre of Finland (VTT), Espoo, Finland.
Department of Regenerative Cardiology, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
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2011 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, no 3, p. 797-809Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.

RESEARCH DESIGN AND METHODS: We addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.

RESULTS: We show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.

CONCLUSIONS: Our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

Place, publisher, year, edition, pages
American Diabetes Association , 2011. Vol. 60, no 3, p. 797-809
National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:oru:diva-63642DOI: 10.2337/db10-0705ISI: 000288060300014PubMedID: 21266330Scopus ID: 2-s2.0-79952437112OAI: oai:DiVA.org:oru-63642DiVA, id: diva2:1169208
Funder
Wellcome trustEU, FP7, Seventh Framework Programme
Note

Funding agencieas:

MRC CORD  

MRC  

BHF  

Spanish Ministry of Science and Innovation SAF2009-07466 BIO BIO2008-04212 

Marato TV3  

Pro-CNIC Foundation  

Fundacion IMABIS 

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-05-08Bibliographically approved

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Oresic, Matej

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