Leptin-Dependent Toll-Like Receptor Expression and Responsiveness in Preadipocytes and Adipocytes

Abstract

Leptin, an adipokine mainly produced by adipocytes, has been well characterized with regard to its regulatory function on immune cells. Thus the question occurred of how adipocytes and preadipocytes interact with the immune system and whether or not this communication is regulated by leptin. With the present study we evaluated the Toll-like receptor (TLR) expression and TLR ligand-specific activation of murine preadipocytes and adipocytes in the presence [wild type (WT), 3T3L1] or absence of leptin (ob/ob) or leptin signaling (db/db). The ob/ob as well as db/db adipocytes and preadipocytes were characterized by a significant up-regulation of TLR1 to -9 expression when compared with WT cells. In WT preadipocytes the TLR responsiveness increased during maturation to adipocytes; however, stimulation of ob/ob and db/db cells resulted in a 10- to 20-fold higher interleukin-6 production. Signaling studies revealed, in addition to the increased TLR expression, alterations in the phosphoinositide 3 kinase signaling cascade in ob/ob and db/db cells as an explanation for this increased responsiveness. In conclusion, the present study indicates the expression and responsiveness of TLR1 to -9 in murine preadipocytes as well as adipocytes, both of which are strongly regulated by the adipokine leptin. In summary, these data further emphasize the role of fat tissue in the immune system.

Nucleotide Oligomerization Domains 1 and 2: Regulation of Expression and Function in Preadipocytes

“…Recent data indicate an additional function for this cell population since they are not only capable of phagocytosis but, furthermore, have been shown to express functional TLR (5). With the present study, the expression and function of the nucleotide-binding site and leucine-rich repeat protein nucleotide oligomerization domains 1 and 2, belonging to the recently discovered family of pattern recognition receptor family localized in the cytoplasm, were characterized in preadipocytes.…”

“…For instance, preadipocytes have the potential to differentiate into the macrophage lineage and have been shown to phagocytose (4). Our group demonstrated that adipocytes and preadipocytes express functional TLR in a leptin-dependent manner (5) suggesting that these cells might belong to the innate immune system.…”

Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice

“…Moreover, several studies have described interplays between TLR signaling and adipokines. In a recent report, significant upregulation of TLR1 to −9 expression in preadipocytes and adipocytes of ob/ob and db/db mice was demonstrated, revealing a strong regulation of TLR expression by leptin (Batra et al, 2007). In a different study, adiponectin has been shown to negatively regulate macrophage-like cell response to TLR ligands (Yamaguchi et al, 2005).…”

Potential association of obesity with IL6 G-174C polymorphism and TTV infections

“…These polymorphisms have been associated with IL6 promoter activity, plasma levels of IL6 [30,31] or ACE [25] and responsiveness of the AT1R [32]. There are several lines of experimental evidences which also support a potential link between TTV infection and inflammation or body weight: 1. transfection of TTV ORF2 into human cell lines could suppress NF-kB activity and transcription of different NF-kB-mediated downstream genes, including IL6 [33]; 2. mice preadipocytes and adipocytes can express Toll-like receptors 9 which can modify IL6 production in response to specific stimuli [34]; TTV DNA can activate Toll-like receptors 9 and can stimulate production and secretion of IL6 by immune cells [35]; 3. some transgenic mice expressing TTV ORF1 [36] or high levels of circulating IL6 [37] present a reduced average body weight and low growth rate; primary infection with TTV can occur early in life [28] and abnormal body weight in early life was associated with risk for later diseases, including obesity [38]. The complex relationship between IL6, fat metabolism and obesity has been examined in many studies, yet the results are still conflicting.…”