Targeting Intestinal Macrophages as a Potential Therapeutic Option in Obesity

Abstract

Background: Chronic inflammation such as systemic or tissue inflammation has been well established in metabolic disease. Although macrophages thereby play a key role, not much is known about the initiation of inflammation. As the gut makes up the largest macrophage reservoir of the body and gastrointestinal changes occur in metabolic disease (altered gut microbiota, increased endotoxin and cytokines), the aim of our study was to assess the role of intestinal macrophages (iMϕs) in obesity. Research Design and Method: IMϕs were isolated from the colon of C57BL/6, germ-free or CCR2-/- mice fed a high fat diet (HFD) or control diet up to three months and characterized by flow cytometry as CCR2+ (“inflammatory”) or CCR2- (resident, anti-inflammatory) subpopulations. For dose-dependent iMϕ depletion, HFD-fed mice were orally treated with 50, 100 or 200 µg/g CSF-1R inhibitor (BLZ945) or its vehicle for up to ten weeks. Results: We found that within one week and up to three months of HFD, inflammatory iMϕs increase, preceding adipose tissue inflammation. Two mouse models protected from metabolic disease - germ-free and CCR2-/- mice - exhibited ≥10-fold lower inflammatory iMϕ numbers when compared to WT mice, suggesting that a threshold of iMϕs is required to elicit metabolic disease. Based on this finding, we depleted macrophages by increasing doses of CSF-1R inhibitor and observed a gradual iMϕ-reduction, which correlated with a dose-dependent improvement in fasting glucose, glucose tolerance and insulin levels. Conclusion: HFD-induced obesity is associated with an increase in inflammatory iMϕs, while mouse models protected from metabolic disease have lower numbers. Accordingly, dose-dependent depletion of iMϕs is accompanied by gradual improvements in glucose metabolism. This suggests that the number of iMϕs is involved in initiation of metabolic disease and thus could serve as a potential therapeutic target in obesity. Disclosure T.V. Rohm: None. S. AlAsfoor: None. A.J. Bosch: None. C. Cavelti-Weder: None.