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This version published online on July 27, 2006
Endocrinology, doi:10.1210/en.2006-0536
A more recent version of this article appeared on November 1, 2006
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Submitted on April 21, 2006
Accepted on July 18, 2006

Preadipocytes mediate LPS-induced inflammation and insulin resistance in primary cultures of newly differentiated human adipocytes

Soonkyu Chung, Kathleen LaPoint, Kristina Martinez, Arion Kennedy, Maria Boysen Sandberg, and Michael K. McIntosh*

Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27402-6170 and Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, DK-5230, Denmark

* To whom correspondence should be addressed. E-mail: mkmcinto{at}uncg.edu.

Recent data suggest that proinflammatory cytokines secreted from adipose tissue contribute to the morbidity associated with obesity. However, characterization of the cell types involved in inflammation and how these cells promote insulin resistance in human adipocytes are unclear. We simulated acute inflammation using the endotoxin lipopolysaccharide (LPS) to define the roles of non-adipocytes in primary cultures of human adipocytes. LPS induction of the mRNA levels of proinflammatory cytokines (e.g. IL-6, TNF-{alpha}, IL-1{beta}) and chemokines (e.g. IL-8, MCP-1) occurred primarily in the non-adipocyte fraction of newly differentiated human adipocytes. Non-adipocytes were characterized as preadipocytes based on their abundant mRNA levels of preadipocyte markers preadipocyte factor-1 (Pref-1) and adipocyte enhancer protein-1 (AEBP-1) and only trace levels of markers for macrophages and myocytes. The essential role of preadipocytes in inflammation was confirmed by modulating the degree of differentiation in the cultures from a ~0-90%. LPS-induced proinflammatory cytokine/chemokine expression and nuclear factor kappa B (NF{kappa}B) and mitogen activated protein kinase (MAPK) signaling decreased as differentiation increased. LPS-induced cytokine/chemokine expression in preadipocytes was associated with 1) decreased adipogenic gene expression, 2) decreased ligand-induced activation of a peroxisome proliferator activated receptor (PPAR) {gamma} reporter construct and increased phosphorylation of PPAR{gamma}, and 3) decreased insulin-stimulated glucose uptake. Collectively, these data demonstrate that LPS induces NF{kappa}B- and MAPK-dependent proinflammatory cytokine/chemokine expression primarily in preadipocytes, which triggers the suppression of PPAR{gamma} activity and insulin responsiveness in human adipocytes.




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