Published Online
on January 28, 2008

A more recent version of this article appeared on February 12, 2008

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Submitted on June 26, 2007
Accepted on November 27, 2007

Remodeling Phenotype of Human Subcutaneous Adipose Tissue Macrophages

V. Bourlier PhD^*, A. Zakaroff-Girard PhD, A. Miranville PhD, S. De Barros MSc, M. Maumus MSc, C. Sengenes PhD, J. Galitzky PhD, M. Lafontan PhD, F. Karpe MD, PhD, K. N. Frayn PhD, ScD, and A. Bouloumié PhD

From the Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France (V.B., A.Z.-G., S.D.B., M.M., C.S., J.G., M.L., A.B.); Université Toulouse III Paul-Sabatier, Institut de Médecine Moléculaire de Rangueil, Equipe No. 1 AVENIR, Toulouse, France (V.B., A.Z.-G., S.D.B., M.M., C.S., J.G., M.L., A.B.); Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK (F.K., K.N.F); and Department of Cardiovascular Physiology, J.-W. Goethe University, Frankfurt, Germany (A.M.).

^* To whom correspondence should be addressed. E-mail: virginie.bourlier{at}toulouse.inserm.fr.

Background—Adipose tissue macrophages (ATMs) have become a focus of attention recently because they have been shown to accumulate with an increase in fat mass and to be involved in the genesis of insulin resistance in obese mice. However, the phenotype and functions of human ATMs are still to be defined.

Methods and Results—The present study, performed on human subcutaneous AT, showed that ATMs from lean to overweight individuals are composed of distinct macrophage subsets based on the expression of several cell surface markers: CD45, CD14, CD31, CD44, HLA-DR, CD206, and CD16, as assessed by flow cytometry. ATMs isolated by an immunoselection protocol showed a mixed expression of proinflammatory (tumor necrosis factor-, interleukin-6 [IL-6], IL-23, monocyte chemoattractant protein-1, IL-8, cyclooxygenase-2) and antiinflammatory (IL-10, transforming growth factor-, alternative macrophage activation–associated cc chemokine-1, cyclooxygenase-1) factors. Fat mass enlargement is associated with accumulation of the CD206⁺/CD16^- macrophage subset that exhibits an M2 remodeling phenotype characterized by decreased expression of proinflammatory IL-8 and cyclooxygenase-2 and increased expression of lymphatic vessel endothelial hyaluronan receptor-1. ATMs specifically produced and released matrix metalloproteinase-9 compared with adipocytes and capillary endothelial cells, and secretion of matrix metalloproteinase-9 from human AT in vivo, assessed by arteriovenous difference measurement, was correlated with body mass index. Finally, ATMs exerted a marked proangiogenic effect on AT-derived endothelial and progenitor cells.

Conclusions—The present results showed that the ATMs that accumulate with fat mass development exhibit a particular M2 remodeling phenotype. ATMs may be active players in the process of AT development through the extension of the capillary network and in the genesis of obesity-associated cardiovascular pathologies.

Key words: angiogenesis • inflammation • leukocytes • metalloproteinases • obesity

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