Characterization of the long pentraxin PTX3 as a TNFα-induced secreted protein of adipose cells

Anissa Abderrahim-Ferkoune,Olivier Bezy,Chiara Chiellini,Margherita Maffei,Paul Grimaldi,Frédéric Bonino,Naïma Moustaid-Moussa,Fabio Pasqualini,Alberto Mantovani,Gérard Ailhaud,Ez-Zoubir Amri

doi:10.1194/jlr.m200382-jlr200

Abstract

Exposure of preadipocytes to long-chain fatty acids induces the expression of several markers of adipocyte differentiation. In an attempt to identify novel genes and proteins that are regulated by fatty acids in preadipocytes, we performed a substractive hybridization screening and identified PTX3, a protein of the pentraxin family. PTX3 mRNA expression is transient during adipocyte differentiation of clonal cell lines and is absent in fully differentiated cells. Stable overexpression of PTX3 in preadipocytes has no effect on adipocyte differentiation. In line with this, PTX3 mRNA is expressed in the stromal-vascular fraction of adipose tissue, but not in the adipocyte fraction; however, in 3T3-F442A adipocytes, the PTX3 gene can be reinduced by tumor necrosis factor alpha (TNFalpha) in a dose-dependent manner. This effect is accompanied by PTX3 protein secretion from both 3T3-F442A adipocytes and explants of mouse adipose tissue. PTX3 mRNA levels are found to be higher in adipose tissue of genetically obese mice versus control mice, consistent with their increased TNFalpha levels. In conclusion, PTX3 appears as a TNFalpha-induced protein that provides a new link between chronic low-level inflammatory state and obesity.

Highlights

Exposure of preadipocytes to long-chain fatty acids induces the expression of several markers of adipocyte differentiation
Secretion of cytokines in adipose tissue is not confined to adipocytes, as we have previously reported that preadipocytes secrete leukemia inhibitory factor (LIF) transiently at a time when their cognate cell surface receptor (LIF-R) is expressed [17]
The PTX3 gene encodes a 42 kDa glycoprotein with a carboxy-terminal half that shares high homology with the entire sequence of C-reactive protein (CRP) and serum amyloid protein, which are acute-phase proteins of the pentraxin family [28,29,30], whereas the NH2-terminal part does not show any significant homology with other known proteins

Summary

Introduction

Exposure of preadipocytes to long-chain fatty acids induces the expression of several markers of adipocyte differentiation. PTX3 mRNA is expressed in the stromal-vascular fraction of adipose tissue, but not in the adipocyte fraction; in 3T3-F442A adipocytes, the PTX3 gene can be reinduced by tumor necrosis factor ␣ (TNF␣) in a dose-dependent manner. An increasing body of evidence correlates the obese phenotype with chronically elevated systemic levels of acute-phase reactants and inflammatory cytokines [1,2,3]. The role of these reactants has remained largely unknown, TNF␣ and IL-6 have been shown to inhibit insulin signaling and to induce both hypertriglyceridemia and endothelial activation [11,12,13] These observations suggest strongly that adipose tissue through adipocytes is an important determinant of a chronic lowlevel inflammatory state [14,15,16]. We show that expression of the PTX3 gene is elevated in mouse models of monogenic obesity, strongly suggesting that PTX3 provides a new link between the chronic low-level inflammatory state and obesity

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