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Chronic inflammation is considered a causal risk factor predisposing to insulin resistance. However, evidence is accumulating that inflammation confined to the liver may not be causal to metabolic dysfunction. To investigate this, we assessed if hepatic inflammation explains the predisposition towards insulin resistance in low-density lipoprotein receptor knock-out (Ldlr−/−) mice. For this, wild type (WT) andLdlr−/−mice were fed a chow diet, a high fat (HF) diet, or a high fat, high cholesterol (HFC) diet for 2 weeks. Plasma lipid levels were elevated in chow-fedLdlr−/−mice compared to WT mice. Although short-term HF or HFC feeding did not result in body weight gain and adipose tissue inflammation, dyslipidemia was worsened inLdlr−/−mice compared to WT mice. In addition, dyslipidemic HF-fedLdlr−/−mice had a higher hepatic glucose production rate than HF-fed WT mice, while peripheral insulin resistance was unaffected. This suggests that HF-fedLdlr−/−mice suffered from hepatic insulin resistance. While HFC-fedLdlr−/−mice displayed the anticipated increased hepatic inflammation, this did neither exacerbate systemic nor hepatic insulin resistance. Therefore, our results show that hepatic insulin resistance is unrelated to cholesterol-induced hepatic inflammation inLdlr−/−mice, indicating that hepatic inflammation may not contribute to metabolic dysfunction per se.

In Crohn's disease (CD), chronic gut inflammation leads to loss of mucosal barrier integrity. Subsequent leakage of IgG to the gut could produce an increase of IgG coating of intestinal bacteria. We investigated if there is more IgG coating in patients than in volunteers and whether this is dependent on the host IgG response or on the gut bacteria. Fecal and serum samples were obtained from 23 CD patients and 11 healthy volunteers. Both thein vivoIgG-coated fecal bacteria andin vitroIgG coating after serum addition were measured by flow cytometry and related to disease activity. The bacterial composition in feces was determined using fluorescencein situhybridization. The IgG-binding capacities ofEscherichia colistrains isolated from feces of patients and volunteers were assessed. The results showed that thein vivoIgG-coated fraction of fecal bacteria of patients was slightly larger than that of volunteers but significantly larger after incubation with either autologous or heterologous serum. This was dependent on the bacteria and independent of disease activity or the serum used. The presence of moreEnterobacteriaceaeand fewer faecalibacteria in patient feces was confirmed.E. coliisolates from patients bound more IgG than isolates from volunteers (P< 0.05) after the addition of autologous serum. Together, these results indicate that CD patients have more IgG-binding gut bacteria than healthy volunteers. We showed that the level of IgG coating depends on the bacteria and not on the serum used. Furthermore, CD patients have a strong specific immune response to their ownE. colibacteria.

Low-grade inflammation and steatosis are strongly associated with non-alcoholic fatty liver disease (NAFLD), the hepatic component of the metabolic syndrome. Macrophage colony stimulating factor (M-CSF) plays a key role in inflammation through its effects on macrophage development and function. Although macrophages have been proposed to play an active role in obesity, the role of macrophages in the development of NAFLD is still a matter of debate.

Features of the metabolic syndrome, such as dyslipidaemia and inflammation, are risk factors contributing to insulin resistance and type 2 diabetes. However, little is known regarding the contribution of these features in the development of insulin resistance in the absence of obesity. We hypothesized that insulin resistance can develop without body weight gain because of dyslipidaemia and inflammation.

Objective: It is generally assumed that hepatic inflammation in obesity is linked to the pathogenesis of insulin resistance. Several recent studies have shed doubt on this view, which questions the causality of this association. This study focuses on Kupffer cell-mediated hepatic inflammation as a possible driver of insulin resistance in the absence and presence of obesity.Methods: We used male mice deficient for the low-density lipoprotein receptor (Ldlr(-/-)) and susceptible to cholesterol-induced hepatic inflammation. Whole body and hepatic insulin resistance was measured in mice fed 4 diets for 2 and 15 weeks, i.e., chow, high-fat (HF), HF-cholesterol (HFC; 0.2% cholesterol) and HF without cholesterol (HFnC). Biochemical parameters in plasma and liver were measured and inflammation was determined using immunohistochemistry and RT-PCR.Results: At 2 weeks, we did not find significant metabolic effects in either diet group, except for the mice fed a HFC diet which showed pronounced hepatic inflammation (p HF, HFnC; p Conclusion: These data show that cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male Ldlr(-/-) mice. This study suggests that Kupffer cell-driven hepatic inflammation is a consequence, not a cause, of metabolic dysfunction in obesity. (C) 2013 Elsevier Ireland Ltd. All rights reserved.