The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.

Background Air pollution has emerged as an unexpected risk factor for diabetes. However, the mechanism behind remains ill-defined. So far, the lung has been considered as the main target organ of air pollution. In contrast, the gut has received little scientific attention. Since air pollution particles can reach the gut after mucociliary clearance from the lungs and through contaminated food, our aim was to assess whether exposure deposition of air pollution particles in the lung or the gut drive metabolic dysfunction in mice. Methods To study the effects of gut versus lung exposure, we exposed mice on standard diet to diesel exhaust particles (DEP; NIST 1650b), particulate matter (PM; NIST 1649b) or phosphate-buffered saline by either intratracheal instillation (30 µg 2 days/week) or gavage (12 µg 5 days/week) over at least 3 months (total dose of 60 µg/week for both administration routes, equivalent to a daily inhalation exposure in humans of 160 µg/m3 PM2.5) and monitored metabolic parameters and tissue changes. Additionally, we tested the impact of the exposure route in a “prestressed” condition (high-fat diet (HFD) and streptozotocin (STZ)). Results Mice on standard diet exposed to particulate air pollutants by intratracheal instillation developed lung inflammation. While both lung and gut exposure resulted in increased liver lipids, glucose intolerance and impaired insulin secretion was only observed in mice exposed to particles by gavage. Gavage with DEP created an inflammatory milieu in the gut as shown by up-regulated gene expression of pro-inflammatory cytokines and monocyte/macrophage markers. In contrast, liver and adipose inflammation markers were not increased. Beta-cell secretory capacity was impaired on a functional level, most likely induced by the inflammatory milieu in the gut, and not due to beta-cell loss. The differential metabolic effects of lung and gut exposures were confirmed in a “prestressed” HFD/STZ model. Conclusions We conclude that separate lung and gut exposures to air pollution particles lead to distinct metabolic outcomes in mice. Both exposure routes elevate liver lipids, while gut exposure to particulate air pollutants specifically impairs beta-cell secretory capacity, potentially instigated by an inflammatory milieu in the gut.

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.

Macrophages have been recognized as key players in non-alcoholic fatty liver disease (NAFLD). Our aim was to assess whether pharmacological attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties, and how this impacts on NAFLD. We analyzed the pro- and anti-inflammatory gene expression of murine macrophages and human monocytes in vitro in the presence or absence of imatinib. In a time-resolved study, we characterized metabolic disease manifestations such as hepatic steatosis, systemic and adipose tissue inflammation as well as lipid and glucose metabolism in obese mice at one and three months of imatinib treatment. Our results showed that imatinib lowered pro-inflammatory markers in murine macrophages and human monocytes in vitro. In obese mice, imatinib reduced TNFα-gene expression in peritoneal and liver macrophages and systemic lipid levels at one month. This was followed by decreased hepatic steatosis, systemic and adipose tissue inflammation and increased insulin sensitivity after three months. As the transcription factor sterol regulatory element-binding protein (SREBP) links lipid metabolism to the innate immune response, we assessed the gene expression of SREBPs and their target genes, which was indeed downregulated in the liver and partially in peritoneal macrophages. In conclusion, targeting both inflammatory and lipogenic pathways in macrophages and liver as shown by imatinib could represent an attractive novel therapeutic strategy for patients with NAFLD.