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


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.

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    • "Suppressor of Cytokine Signaling 3 (SOCS3) is an inflammatory mediator that has also been previously identified to be important in glucose and lipid metabolism, and it has been implicated in the pathogenesis of experimental models of NAFLD (Wang et al. 2009; Ihle 1995; Handy et al. 2011; Brenner et al. 2013; Moschen et al. 2010; Clementi et al. 2009; Ogawa and Kasuga 2008; Ueki et al. 2005; Tilg 2010). In fact, when mice with a liver-specific deletion of Socs3 are fed a high-fat diet, they develop increased liver fat and inflammation compared with control mice (Sachithanandan et al. 2010). "
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    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 · 3.20 Impact Factor
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    • "Causation studies in humans are challenging to conceive and to perform. Comprehensive genetic studies in mice are also arduous, in part due to their long duration, given rodent lifespans (Robertson et al., 2011), and difficulties in the interpretation of conventional knockout and cell depletion experiments (Clementi et al., 2009; Feng et al., 2011; Jin and Flavell, 2013; Orr et al., 2012; Saberi et al., 2009; Tanti et al., 2012). Therefore, the causative role of macrophages and the basic molecular mechanisms that may underlie their contribution to the disruption of homeostasis and lifespan reduction remain difficult to elucidate. "
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    ABSTRACT: Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling, reduced insulin sensitivity, hyperglycemia, and a shorter lifespan. Drosophila macrophages produced the JAK-STAT-activating cytokine upd3, in a scavenger-receptor (crq) and JNK-dependent manner. Genetic depletion of macrophages or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-κB signaling made no contribution to the phenotype observed. These results identify an evolutionarily conserved "scavenger receptor-JNK-type 1 cytokine" cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Immunity 12/2014; 42(1). DOI:10.1016/j.immuni.2014.12.023 · 21.56 Impact Factor
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    • "Resident tissue macrophages aid in tissue homeostasis, but obesity can promote low-grade inflammation in insulin sensitive tissues. Conflicting literature has complicated our understanding of the role of KCs and hepatic inflammation in lipid homeostasis in obese mouse livers [12], [22], [24], [28]. Thus, we sought to investigate the mechanism whereby KCs and KC-derived cytokines regulate whole body and hepatic lipid metabolism in two mouse models of obesity after clodronate liposome-mediated KC depletion. "
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    ABSTRACT: Non-alcoholic fatty liver disease is prevalent in human obesity and type 2 diabetes, and is characterized by increases in both hepatic triglyceride accumulation (denoted as steatosis) and expression of pro-inflammatory cytokines such as IL-1β. We report here that the development of hepatic steatosis requires IL-1 signaling, which upregulates Fatty acid synthase to promote hepatic lipogenesis. Using clodronate liposomes to selectively deplete liver Kupffer cells in ob/ob mice, we observed remarkable amelioration of obesity-induced hepatic steatosis and reductions in liver weight, triglyceride content and lipogenic enzyme expressions. Similar results were obtained with diet-induced obese mice, although visceral adipose tissue macrophage depletion also occurred in response to clodronate liposomes in this model. There were no differences in the food intake, whole body metabolic parameters, serum β-hydroxybutyrate levels or lipid profiles due to clodronate-treatment, but hepatic cytokine gene expressions including IL-1β were decreased. Conversely, treatment of primary mouse hepatocytes with IL-1β significantly increased triglyceride accumulation and Fatty acid synthase expression. Furthermore, the administration of IL-1 receptor antagonist to obese mice markedly reduced obesity-induced steatosis and hepatic lipogenic gene expression. Collectively, our findings suggest that IL-1β signaling upregulates hepatic lipogenesis in obesity, and is essential for the induction of pathogenic hepatic steatosis in obese mice.
    PLoS ONE 09/2014; 9(9):e107265. DOI:10.1371/journal.pone.0107265 · 3.23 Impact Factor
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