Abstract
The gut microbiota has been proposed as an environmental factor that affects the development of metabolic and inflammatory diseases in mammals. Recent reports indicate that gut bacteria-derived lipopolysaccharide (LPS) can initiate obesity and insulin resistance in mice; however, the molecular interactions responsible for microbial regulation of host metabolism and mediators of inflammation have not been studied in detail. Hepatic serum amyloid A (SAA) proteins are markers and proposed mediators of inflammation that exhibit increased levels in serum of insulin-resistant mice. Adipose tissue-derived SAA3 displays monocyte chemotactic activity and may play a role in metabolic inflammation associated with obesity and insulin resistance. To investigate a potential mechanistic link between the intestinal microbiota and induction of proinflammatory host factors, we performed molecular analyses of germ-free, conventionally raised and genetically modified Myd88−/− mouse models. SAA3 expression was determined to be significantly augmented in adipose (9.9±1.9-fold; P<0.001) and colonic tissue (7.0±2.3-fold; P<0.05) by the presence of intestinal microbes. In the colon, we provided evidence that SAA3 is partially regulated through the Toll-like receptor (TLR)/MyD88/NF-kappaB signaling axis. We identified epithelial cells and macrophages as cellular sources of SAA3 in the colon and found that colonic epithelial expression of SAA3 may be part of an NF-kappaB-dependent response to LPS from gut bacteria. In vitro experiments showed that LPS treatments of both epithelial cells and macrophages induced SAA3 expression (27.1±2.5-fold vs. 1.6±0.1-fold, respectively). Our data suggest that LPS, and potentially other products of the indigenous gut microbiota, might elevate cytokine expression in tissues and thus exacerbate chronic low-grade inflammation observed in obesity.
Highlights
Genetic variations influence individual susceptibility to obesity and insulin resistance, lifestyle and environmental factors play key roles in the development of these diseases [1]
To address whether expression of serum amyloid A (SAA) isoforms in adipose tissue could be altered by the microbiota, we assessed SAA1/2 and Serum Amyloid A3 (SAA3) mRNAs by quantitative real-time PCR in GF and conventionally raised (CONV-R) Swiss-Webster mice (n = 10 per group). mRNA levels of SAA3 in adipose tissue were significantly higher (9.9-fold) in CONV-R mice compared with GF mice (Figure 1A)
The staining pattern suggest that adipocytes are positive for SAA3, consistent with a previous report [17]; interstitial macrophages may contribute to SAA3 expression in adipose tissue [8]
Summary
Genetic variations influence individual susceptibility to obesity and insulin resistance, lifestyle and environmental factors play key roles in the development of these diseases [1]. The gut microbiota has recently been suggested as one such environmental factor [2,3]. Obesity and the metabolic syndrome are associated with lowgrade ‘metabolic’ inflammation [10] and recent data suggest that lipopolysaccharide (LPS) derived from the gut microbiota contributes to the increased development of adipose tissue and impaired glucose tolerance [11,12]. Mice deficient in TLR4 or its co-receptor CD14 are protected against diet-induced obesity and insulin resistance [14,15]. It is not clear which inflammatory molecules are induced by LPS or other products of the gut microbiota
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
