Background: Obesity is a global health burden and a chronic life-threatening disease associated with low-grade inflammation and metabolic dysfunction. The intestinal immune system has emerged as a central regulator of systemic inflammation and glucose homeostasis. Inhibition of gut immune cell trafficking may therefore represent a novel mechanism linking intestinal immunity to metabolic dysfunction. The mucosal adhesion molecule MAdCAM-1 mediates the recruitment of α4β7-expressing lymphocytes to the intestinal mucosa, but its contribution to obesity-associated inflammation and metabolic dysfunction remains unknown. The aim of this study was to investigate the effect of MAdCAM-1-deficiency on metabolism and obesity.
Methods: Male MAdCAM-1–/– mice (n=13) and wild type mice (n=10) were fed a high-fat diet (HFD) and compared to control groups (MAdCAM-1–/–, n=5, MAdCAM-1 WT, n=6) fed chow diet for 20 weeks. Body weight, fasted blood glucose levels, and insulin tolerance (ITT) were assessed. Systemic immune cell profiling was performed by multicolor Aurora flow cytometry (FACS) of blood, white adipose tissue (WAT), liver, kidney, spleen, and bone marrow. In addition, intestinal immune cell subsets were analyzed in the lamina propria (LP) and intraepithelial lymphocytes (IEL) of the small intestine.
Results: Despite similar body weight gain under HFD, MAdCAM-1–/– mice showed a non-significant trend to reduced fasting blood glucose levels (10.48 ± 1.35 vs. 7.98 ± 0.41 mmol/l in WT vs. MAdCAM-1–/– mice, p=0.08). Furthermore, mice lacking MAdCAM-1 had improved insulin tolerance compared to WT mice (ITT AUC of blood glucose levels over time: 742.3 ± 0.48 vs. 985.4 ± 0.37, p=0.02). FACS analysis revealed a reduction of Ly6Chigh monocytes in the blood (33%), WAT (49%) and in the kidney (28%) in MAdCAM-1–/– mice vs. WT mice. In WT mice, obesity induced by HFD led to a distinct redistribution of intestinal immune cells, characterized by a 11-fold increase in lamina propria (LP) leukocytes and a reduction in intraepithelial lymphocytes (IEL) compared to control mice without obesity (chow diet), indicating obesity-associated intestinal immune cell activation.
Conclusion: These data suggest that HFD-induced obesity shifts intestinal immune cells from the epithelial layer to the lamina propria, which might indicate gut immune cell activation. Despite similar body weight under HFD, MAdCAM-1 deficiency protected against obesity-induced metabolic dysfunction by improving insulin sensitivity and limiting inflammatory monocyte expansion. MAdCAM-1 associated intestinal inflammation might be a novel potential therapeutic target in obesity and metabolic dysfunction.
