Abstract
BackgroundObesity induced by high fat (HF) diet is associated with inflammation which contributes to development of insulin resistance. Most prior studies have focused on adipose tissue as the source of obesity-associated inflammation. Increasing evidence links intestinal bacteria to development of diet-induced obesity (DIO). This study tested the hypothesis that HF western diet and gut bacteria interact to promote intestinal inflammation, which contributes to the progression of obesity and insulin resistance.Methodology/Principal FindingsConventionally raised specific-pathogen free (CONV) and germ-free (GF) mice were given HF or low fat (LF) diet for 2–16 weeks. Body weight and adiposity were measured. Intestinal inflammation was assessed by evaluation of TNF-α mRNA and activation of a NF-κBEGFP reporter gene. In CONV but not GF mice, HF diet induced increases in body weight and adiposity. HF diet induced ileal TNF-α mRNA in CONV but not GF mice and this increase preceded obesity and strongly and significantly correlated with diet induced weight gain, adiposity, plasma insulin and glucose. In CONV mice HF diet also resulted in activation of NF-κBEGFP in epithelial cells, immune cells and endothelial cells of small intestine. Further experiments demonstrated that fecal slurries from CONV mice fed HF diet are sufficient to activate NF-κBEGFP in GF NF-κBEGFP mice.Conclusions/SignificanceBacteria and HF diet interact to promote proinflammatory changes in the small intestine, which precede weight gain and obesity and show strong and significant associations with progression of obesity and development of insulin resistance. To our knowledge, this is the first evidence that intestinal inflammation is an early consequence of HF diet which may contribute to obesity and associated insulin resistance. Interventions which limit intestinal inflammation induced by HF diet and bacteria may protect against obesity and insulin resistance.
Highlights
It is widely accepted that obesity is associated with lowgrade chronic inflammation and that inflammation contributes to risk of insulin resistance and type 2 diabetes as well as other detrimental health consequences linked to obesity [1,2,3]
GF mice fed high fat (HF) vs low fat (LF) diet did not differ in body weight at any time point (P.0.05 at all time points) and GF mice fed either HF or LF diet exhibited body weights over the 16 week period that were indistinguishable from Conventionally raised specific-pathogen free (CONV) mice on LF diet (Figure 1A and B)
By week 6, CONV mice on HF diet had significantly increased percent body fat and fat mass compared with the animals on LF diet and this increase was more dramatic by 16 weeks (P,0.001) (Figure 1C and E)
Summary
It is widely accepted that obesity is associated with lowgrade chronic inflammation and that inflammation contributes to risk of insulin resistance and type 2 diabetes as well as other detrimental health consequences linked to obesity [1,2,3]. Multiple studies have demonstrated that diet-induced obesity is associated with increased expression of a number of proinflammatory cytokines or biomarkers of inflammation in adipose tissue [9,10]. A number of studies support a concept that inflammation may derive from the accumulation of activated macrophages within adipose tissue and, surrounding enlarged adipocytes of obese animals or humans [10,11]. The source of adipocyte-derived macrophages in obesity is not known but HF diet induces expression of adhesion molecules in adipose tissue, which are associated with leukocyte migration and adherence [9]. This study tested the hypothesis that HF western diet and gut bacteria interact to promote intestinal inflammation, which contributes to the progression of obesity and insulin resistance
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