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Adipocyte-Derived Serum Amyloid A3 and Hyaluronan Play a Role in Monocyte Recruitment and Adhesion

¹ Department of Medicine, University of Washington, Seattle, Washington
² Hope Heart Program, Benaroya Research Institute, Seattle, Washington

Address correspondence and reprint requests to Alan Chait, MD, Division of Metabolism, Endocrinology,Nutrition, Box 356426, University of Washington, Seattle, WA 98195-6426. E-mail: achait{at}u.washington.edu

Abbreviations: CCR2, C-C motif chemokine receptor 2;; CRP, C-reactive protein;; ELISA, enzyme-linked immunosorbent assay;; EMSA, electromobility shift assay;; FITC, fluorescein isothiocyanate;; FMLP, formyl-methionyl-leucyl-phenylalanine;; GAPDH, glyceraldehyde-3-phosphate dehydrogenase;; HABP, hyaluronan binding protein;; HAS, hyaluronan synthase;; IL, interleukin;; MALDI-TOF, matrix-assisted laser desorption ionization/time of flight;; MCP-1, monocyte chemoattractant protein-1;; NF-B, nuclear factor-B;; PPAR, peroxisome proliferator–activated receptor;; PPRE, PPAR response element;; SAA, serum amyloid A;; siRNA, small interfering RNA;; TNF-, tumor necrosis factor-;; WGA, wheat germ agglutinin

Obesity is characterized by adipocyte hypertrophy and macrophage accumulation in adipose tissue. Monocyte chemoattractant protein-1 (MCP-1) plays a role in macrophage recruitment into adipose tissue. However, other adipocyte-derived factors, e.g., hyaluronan and serum amyloid A (SAA), can facilitate monocyte adhesion and chemotaxis, respectively. The objective was to test the potential involvement of these factors in macrophage recruitment. Differentiated 3T3-L1 adipocytes made hypertrophic by growth in high glucose conditions were used to study SAA and hyaluronan regulation in vitro. Two mouse models of obesity were used to study their expression in vivo. Nuclear factor-B was upregulated and peroxisome proliferator–activated receptor (PPAR) was downregulated in hypertrophic 3T3-L1 cells, with increased expression of SAA3 and increased hyaluronan production. Rosiglitazone, a PPAR agonist, reversed these changes. Hypertrophic adipocytes demonstrated overexpression of SAA3 and hyaluronan synthase 2 in vitro and in vivo in diet-induced and genetic obesity. SAA and hyaluronan existed as part of a complex matrix that increased the adhesion and retention of monocytes. This complex, purified by binding to a biotinylated hyaluronan binding protein affinity column, also showed monocyte chemotactic activity, which was dependent on the presence of SAA3 and hyaluronan but independent of MCP-1. We hypothesize that adipocyte hypertrophy leads to increased production of SAA and hyaluronan, which act in concert to recruit and retain monocytes, thereby leading to local inflammation in adipose tissue.

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