Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 09/2009; 1792(11):1062-72. DOI: 10.1016/j.bbadis.2009.08.007
Source: PubMed

ABSTRACT While adipose tissue-associated macrophages contribute to development of chronic inflammation and insulin resistance of obesity, little is known about the role of hepatic Kupffer cells in this environment. Here we address the impact of Kupffer cell ablation using clodronate-encapsulated liposome depletion in a diet-induced obese (DIO) and insulin resistant mouse model. Hepatic expression of macrophage markers measured by realtime RT-PCR remained unaltered in DIO mice despite characteristic expansion of adipose tissue-associated macrophages. DIO mouse livers displayed increased expression of alternative activation markers but unaltered proinflammatory cytokine expression when compared to lean mice. Kupffer cell ablation reduced hepatic anti-inflammatory cytokine IL-10 mRNA expression in lean and DIO mice by 95% and 84%, respectively. Despite decreased hepatic IL-6 gene expression after ablation in lean and DIO mice, hepatic STAT3 phosphorylation, Socs3 and acute phase protein mRNA expression increased. Kupffer cell ablation in DIO mice resulted in additional hepatic triglyceride accumulation and a 30-40% reduction in hepatic insulin receptor autophosphorylation and Akt activation. Implicating systemic loss of IL-10, high-fat-fed IL-10 knockout mice also displayed increased hepatic STAT3 signaling and hepatic triglyceride accumulation. Insulin signaling was not altered, however. In conclusion, Kupffer cells are a major source of hepatic IL-10 expression, the loss of which is associated with increased STAT3-dependent signaling and steatosis. One or more additional factors appear to be required, however, for the Kupffer cell-dependent protective effect on insulin receptor signaling in DIO mice.

Download full-text


Available from: Nico Van Rooijen, Jul 02, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of human hepatic disease and feeding mice a High-Fat, High-Caloric (HFHC) diet is a standard model of NAFLD. To better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. 265 (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 weeks. eQTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1s and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11(A/J)/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (P < 0.05), while C57BL/6J-Chr 1(A/J)/ NaJ mice retained the C57BL/6J phenotype. In addition, we replicated the eQTLs on Chr 1 and 12 (LOD scores ≥ 3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and 11, and consomic mice confirmed that replacing the C57BL/6J Chr 11 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases. Copyright © 2015 Author et al.
    G3-Genes Genomes Genetics 01/2015; 5(4). DOI:10.1534/g3.115.016626 · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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<0.05) but normal insulin sensitivity. At 15 weeks, a significant increase in insulin levels, HOMA-IR, and hepatic insulin resistance was observed in mice fed a HFC, HFnC, and HF diet compared to chow-fed mice (p<0.05). Regardless of the level of hepatic inflammation (HFC > HF, HFnC; p<0.05) insulin resistance in mice fed HFC was no worse compared to mice on a HFnC and HF diet. 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.
    Atherosclerosis 01/2013; 232(2). DOI:10.1016/j.atherosclerosis.2013.11.074 · 3.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic and immune-related pathways intersect at numerous levels. Their common regulation is effectuated by several hormonal signaling routes that involve specific nuclear hormone receptors and adipokines. Glucocorticoids and leptin are hormones that play a key role in coordinating energy metabolism and food-seeking behavior during energy deficiency as does the nuclear hormone receptor Peroxisome Proliferator Activated Receptor α (PPARalpha). Importantly, the glucocorticoid, leptin, and PPARalpha signaling routes share a profound role in governing inflammation and other immune-related processes. Using specific examples, this chapter aims at illustrating the interplay between metabolism and immunity/inflammation by discussing common endocrine and transcriptional regulators of metabolism and inflammation and by highlighting the interaction between macrophages and metabolically active cells in liver and adipose tissue. Convergence of metabolic and immune signaling is likely at least partially driven by the evolutionary need during times of food insufficiency to minimize loss of energy to processes that are temporarily nonessential to the survival of the species.
    Results and problems in cell differentiation 01/2010; 52:13-25. DOI:10.1007/978-3-642-14426-4_2