Endocrine Abstracts (2004) 7 P54

TLR mediated activation of the innate immune response in human adipocytes with associated down-regulation of adiponectin secretion and elevated TNF-alpha and IL-6 levels

FFM Fisher, S Creely, C Burman, AL Harte, R Chetty, G Valsamakis, PG McTernan & S Kumar

Unit for Diabetes and Metabolism, Warwick Medical School, University of Warwick, Coventry, UK.

Type 2 diabetes (T2DM) is associated with insulin resistance and chronic sub-clinical inflammation. Pro-inflammatory cytokines produced from adipose tissue are secreted as part of the innate immune response and also associated with insulin resistance. In contrast, adipocyte derived adiponectin is associated with insulin sensitivity and also has anti-inflammatory properties. Hence fat may represent a site for mediating the innate immune response. We therefore investigated a mechanism for the observed reduction in adiponectin secretion in obesity and T2DM. Our studies: (1) determined the protein expression of components of the innate immune system in human adipocytes (2) and assessed the activation of the innate immune system as a mechanism for the regulation of adiponectin. Subcutaneous adipocytes were isolated from subjects (BMI: 24.7plus/minu(SD)4.9; n=10) and western blotting was performed to determine protein expression. The results indicated that subcutaneous adipocytes expressed several key components of the innate immune pathway (toll like receptors (TLR) 2 and 4, NFkappaB, IkappaB-alpha and lipopolysaccharide (LPS) binding protein). Furthermore, in vitro studies in human subcutaneous adipocytes examined the effects of bacterial (LPS) and fungal (zymosan) agents on the regulation of pro-inflammatory agents (IL-6 and TNF-alpha) as well as adiponectin. These findings showed an increase in secretion of pro-inflammatory cytokines TNF-alpha (p=0.003 and p=0.047, respectively) and IL-6 (p=0.003 and p=0.002, respectively) whilst a significant reduction in adiponectin secretion (bacterial: p=0.003 and fungal: p=0.002) was observed. This response to the antigenic agents also increased the expression of TLR-2, a known mediator of innate immune activity. In summary, adipocytes contain key components of the innate immune system, substantiating the role of adipose tissue in the inflammatory response. Furthermore, subcutaneous adipocytes react to antigenic stimuli by secreting pro-inflammatory factors such as TNF-alpha and IL-6, with an associated reduction of adiponectin secretion. This response may be mediated through TLR-2 and TLR-4.

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