Journal Article

The CCR2 Inhibitor Propagermanium Attenuates Diet-Induced Insulin Resistance, Adipose Tissue Inflammation and Non-Alcoholic Steatohepatitis

Kleemann, Robert, Mulder, Petra, van den Hoek, Anita M.

2017

Overview

Obese patients with chronic inflammation in white adipose tissue (WAT) have an increased risk of developing non-alcoholic steatohepatitis (NASH). The C-C chemokine receptor-2 (CCR2) has a crucial role in the recruitment of immune cells to WAT and liver, thereby promoting the inflammatory component of the disease. Herein, we examined whether intervention with propagermanium, an inhibitor of CCR2, would attenuate tissue inflammation and NASH development. Male C57BL/6J mice received a high-fat diet (HFD) for 0, 6, 12 and 24 weeks to characterize the development of early disease symptoms of NASH, i.e. insulin resistance and WAT inflammation (by hyperinsulinemic-euglycemic clamp and histology, respectively) and to define the optimal time point for intervention. In a separate study, mice were pretreated with HFD followed by propagermanium treatment (0.05% w/w) after 6 weeks (early intervention) or 12 weeks (late intervention). NASH was analyzed after 24 weeks of diet feeding. Insulin resistance in WAT developed after 6 weeks of HFD, which was paralleled by modest WAT inflammation. Insulin resistance and inflammation in WAT intensified after 12 weeks of HFD, and preceded NASH development. The subsequent CCR2 intervention experiment showed that early, but not late, propagermanium treatment attenuated insulin resistance. Only the early treatment significantly decreased Mcp-1 and CD11c gene expression in WAT, indicating reduced WAT inflammation. Histopathological analysis of liver demonstrated that propagermanium treatment decreased macrovesicular steatosis and tended to reduce lobular inflammation, with more pronounced effects in the early intervention group. Propagermanium improved the ratio between pro-inflammatory (M1) and anti-inflammatory (M2) macrophages, quantified by CD11c and Arginase-1 gene expression in both intervention groups. Overall, early propagermanium administration was more effective to improve insulin resistance, WAT inflammation and NASH compared to late intervention. These data suggest that therapeutic interventions for NASH directed at the MCP-1/CCR2 pathway should be initiated early.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adipose tissue / Adipose Tissue - drug effects / Adipose Tissue - metabolism / Adipose Tissue - pathology / Alcoholic liver diseases / Analysis / Animals / Anti-Inflammatory Agents - pharmacology / Anti-Inflammatory Agents - therapeutic use / Arginase / Arginase - genetics / Arginase - metabolism / Attenuation / Biology and Life Sciences / Body fat / Care and treatment / CC chemokine receptors / CCR2 protein / CD11 Antigens - genetics / CD11 Antigens - metabolism / CD11c antigen / Chemokine CCL2 - genetics / Chemokine CCL2 - metabolism / Development and progression / Diet / Diet, High-Fat - adverse effects / Gene expression / Glucose / High fat diet / Histology / Immune system / Inflammation / Inhibitors / Insulin / Insulin Resistance / Intervention / Liver / Macrophages / Male / Medical research / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Monocyte chemoattractant protein 1 / Non-alcoholic Fatty Liver Disease - drug therapy / Non-alcoholic Fatty Liver Disease - etiology / Non-alcoholic Fatty Liver Disease - metabolism / Obesity / Organometallic Compounds - pharmacology / Organometallic Compounds - therapeutic use / Receptors, CCR2 - antagonists & inhibitors / Receptors, CCR2 - metabolism / Risk factors / Rodents / Steatosis / Therapeutic applications