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, 5 (8), e12191

High-fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates With Obesity and Insulin Resistance in Mouse

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High-fat Diet: Bacteria Interactions Promote Intestinal Inflammation Which Precedes and Correlates With Obesity and Insulin Resistance in Mouse

Shengli Ding et al. PLoS One.

Abstract

Background: Obesity 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 findings: Conventionally 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-alpha mRNA and activation of a NF-kappaB(EGFP) reporter gene. In CONV but not GF mice, HF diet induced increases in body weight and adiposity. HF diet induced ileal TNF-alpha 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-kappaB(EGFP) 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-kappaB(EGFP) in GF NF-kappaB(EGFP) mice.

Conclusions/significance: Bacteria 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Body weight and fat mass in CONV or GF mice on HF/LF diet.
Histograms show mean ± SE. a: P<0.05 vs LF group at the same time point; b: P<0.05 vs CONV HF at 2wk and 6wk.
Figure 2
Figure 2. TNF-α mRNA levels in intestine of CONV or GF mice on HF/LF diet.
Histograms show mean ± SE expressed as fold change vs the mean mRNA level in mice fed LF diet for 2 weeks. a: P<0.05 vs CONV LF diet group.
Figure 3
Figure 3. Metabolic measurements in CONV mice fed HF or LF diet.
Data are expressed as mean ± SE; Note that food was withdrawn from mice 4 hours before plasma collection for insulin and glucose assays. a: P<0.05 vs LF group.
Figure 4
Figure 4. White light and EGFP imaging of intestine in CONV NF-κBEGFP mice on HF/LF diet.
White arrow: autofluorescence which is common in proximal colon. A: 2 weeks on HF/LF diet. B: 6 weeks on HF/LF diet. C: >16 weeks on HF/LF diet. Abbreviations: Duo: duodenum; Jej:Jejunum; Ile: ileum; Col:colon.
Figure 5
Figure 5. Imaging of small intestine in NF-κBEGFP mice fed HF/LF diet for 16 weeks.
A, B and C show representative images from 2 different mice given HF diet to illustrate large foci (Peyer's patches/lymphoid aggregates) and smaller foci (throughout the intestine) of NF-κBEGFP expression (white arrows); D shows minimal NF-κBEGFP activation in mice fed LF diet. A: large foci in jejunum (>7.11×magnification). B: large and small foci in ileum (7.11×magnification). C: large and small foci in ileum (7.11×magnification). D: large and small foci in distal ileum (>7.11×magnification).
Figure 6
Figure 6. Representative regions of NF-κBEGFP activation-epithelial cells over lymphoid aggregate, subepithelial cells, cells within blood vessel.
A: NF-κBEGFP activation in cells within blood vessel (10×). B: NF-κBEGFP activation in epithelial cells over lymphoid aggregate (20×). C: NF-κBEGFP activation in epithelial cells over lymphoid aggregate (10×). D: NF-κBEGFP activation in epithelial cells over lymphoid aggregate and subepithelial cells (20×).
Figure 7
Figure 7. Immunostaining for antigenic markers (red) compared with NF-κB (green) and overlay showing colocalization (white arrows).
Figure 8
Figure 8. Immunostaining for antigenic markers (red) and GFP to show absence of co-localization in cells.
(A) macrophages; (B)B cells; (C) neutrophils.
Figure 9
Figure 9. NF-κBEGFP in intestinal tissue of GF mice treated with HF or LF fecal slurry.
Fecal slurry from mice fed HF diet induces NF-κBEGFP expression to a greater extent than fecal slurries from mice fed LF diet (Image representative of observation in 3 pairs of mice) in intestine tissues of GF NF-κBEGFP mice. Abbreviations: Duo: duodenum; Jej:Jejunum; Ile: ileum; Col:colon.

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