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Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.

ABSTRACT: OBJECTIVE: We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity. RESEARCH DESIGN AND METHODS: Expression and regulation of members in the entire chemokine superfamily were evaluated in adipose tissue and isolated adipocytes of obese versus lean mice. Kinetics of adipose tissue macrophage infiltration was characterized by fluorescence-activated cell sorting. The effects of fatty acids on stimulation of chemokine expression in adipocytes and underlying mechanisms were investigated. RESULTS: Six monocyte chemotactic factors were found to be predominantly upregulated in isolated adipocytes versus stromal vascular cells in obese mice for the first time, although most of them were previously reported to be upregulated in whole adipose tissue. In diet-induced obese mice, adipose tissue enlargement, increase of adipocyte number, and elevation of multiple chemokine expression precede the initiation of macrophage infiltration. Free fatty acids (FFAs) are found to be inducers for upregulating these chemokines in 3T3-L1 adipocytes, and this effect can be partially blunted by reducing Toll-like receptor 4 expression. FFAs induce expression of monocyte chemotactic factors in adipocytes via both transcription-dependent and -independent mechanisms. In contrast to the reported role of JNK as the exclusive mediator of FFA-induced monocyte chemoattractant protein-1 (MCP-1) expression in macrophages, we show a novel role of inhibitor of kappaB kinase-beta (IKKbeta) in mediating FFA-induced upregulation of all six chemokines and a role of JNK in FFA-induced upregulation of MCP-1 and MCP-3. CONCLUSIONS: Multiple chemokines derived from adipocytes might contribute to obesity-related WAT macrophage infiltration with FFAs as potential triggers and involvement of both IKKbeta and JNK pathways.

SUBMITTER: Jiao P

PROVIDER: S-EPMC2606857 | biostudies-other | 2009 Jan

REPOSITORIES: biostudies-other

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Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.

Jiao Ping P Chen Qiu Q Shah Suketu S Du Jing J Tao Bo B Tzameli Iphigenia I Yan Weiqun W Xu Haiyan H

Diabetes 20081003 1

<h4>Objective</h4>We sought to evaluate the entire picture of all monocyte chemotactic factors that potentially contribute to adipose tissue macrophage accumulation in obesity.<h4>Research design and methods</h4>Expression and regulation of members in the entire chemokine superfamily were evaluated in adipose tissue and isolated adipocytes of obese versus lean mice. Kinetics of adipose tissue macrophage infiltration was characterized by fluorescence-activated cell sorting. The effects of fatty a ...[more]

PMID: 18835938

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Project description:Inflammation is an important mediator of obesity-related complications such as the metabolic syndrome but its causes and mechanisms are unknown. As the complement system is a key mediator of inflammation, we studied whether it is activated in acquired obesity in subcutaneous adipose tissue (AT) and isolated adipocytes. We used a special study design of genetically matched controls of lean and heavy groups, rare monozygotic twin pairs discordant for body mass index (BMI) [n = 26, within-pair difference (Δ) in body mass index, BMI >3 kg/m2] with as much as 18 kg mean Δweight. Additionally, 14 BMI-concordant (BMI <3 kg/m2) served as a reference group. The detailed measurements included body composition (DEXA), fat distribution (MRI), glucose, insulin, adipokines, C3a and SC5b-9 levels, and the expression of complement and insulin signaling pathway-related genes in AT and adipocytes. In both AT and isolated adipocytes, the classical and alternative pathway genes were upregulated, and the terminal pathway genes downregulated in the heavier co-twins of the BMI-discordant pairs. The upregulated genes included C1q, C1s, C2, ficolin-1, factor H, receptors for C3a and C5a (C5aR1), and the iC3b receptor (CR3). While the terminal pathway components C5 and C6 were downregulated, its inhibitor clusterin was upregulated. Complement gene upregulation in AT and adipocytes correlated positively with adiposity and hyperinsulinemia and negatively with the expression of insulin signaling-related genes. Plasma C3a, but not SC5b-9, levels were elevated in the heavier co-twins. There were no differences between the co-twins in BMI-concordant pairs. Obesity is associated with increased expression of the early, but not late, complement pathway components and of key receptors. The twins with acquired obesity have therefore an inflated inflammatory activity in the AT. The results suggest that complement is likely involved in orchestrating clearance of apoptotic debris and inflammation in the AT.

Dataset Information

Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.

Publications

Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways.

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