Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity

Taeye, Bart M. De; Novitskaya, Tatiana; McGuinness, Owen P.; Gleaves, Linda A.; Medda, Mousumi; Covington, Joseph W.; Vaughan, Douglas E.

doi:10.1152/ajpendo.00194.2007

Cited by 185 publications

(144 citation statements)

References 52 publications

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“…Of note, recent studies have shown that IL-1b and TNF-a, two proinflammatory Kupffer-cell-derived cytokines, promote steatosis. [38][39][40] We show that liver expression of IL-1b and TNF-a decreases in alcohol-fed mice concurrently treated with JWH-133 and increases in CB2-deficient counterparts. A similar pattern of regulation was also found in our in vitro experiments, therefore suggesting that the reduction in Kupffer-cell production of IL-1b and TNF-a may contribute to the protective effects of CB2 receptors on hepatocyte lipid accumulation.…”

Section: Discussionmentioning

confidence: 79%

“…In rodents exposed to an alcohol diet or a high-fat diet, depletion of Kupffer cells blunts the development of fatty liver. 9,[38][39][40] Furthermore, cocultures of M1-polarized Kupffer cells with hepatocytes promote lipid accumulation into parenchymal cells. 5,6,38,39 In keeping with these data, we show that CM obtained from JWH-133-and LPS-stimulated macrophages reduces lipid accumulation in hepatocytes, compared to CM prepared from macrophages exposed to LPS alone.…”

Section: Discussionmentioning

confidence: 99%

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Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice

et al. 2011

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Activation of Kupffer cells plays a central role in the pathogenesis of alcoholic liver disease. Because cannabinoid CB2 receptors (CB2) display potent anti-inflammatory properties, we investigated their role in the pathogenesis of alcoholic liver disease, focusing on the impact of CB2 on Kupffer cell polarization and the consequences on liver steatosis. Wildtype (WT) mice fed an alcohol diet showed an induction of hepatic classical (M1) and alternative (M2) markers. Cotreatment of alcohol-fed mice with the CB2 agonist, JWH-133, decreased hepatic M1 gene expression without affecting the M2 profile. In keeping with this, genetic ablation of CB2 enhanced hepatic induction of M1 gene signature and blunted the induction of M2 markers. CB2 also modulated alcohol-induced fatty liver, as shown by the reduction of hepatocyte steatosis in JWH-133-treated mice and its enhancement in CB22/2 animals. Studies in isolated Kupffer cells and cultured macrophages further demonstrated that CB2 inhibits M1 polarization and favors the transition to an M2 phenotype. In addition, conditioned-medium experiments showed that preventing M1 polarization in CB2-activated macrophages protects from lipid accumulation in hepatocytes. Heme oxygenase-1 (HO-1) mediated the anti-inflammatory effects of CB2 receptors. Indeed, alcohol-fed mice treated with JWH-133 showed increased hepatic expression of macrophage HO-1, as compared to vehicle-treated counterparts. In keeping with this, JWH-133 induced HO-1 expression in cultured macrophages, and the HO-1 inhibitor, zinc protoporphyrin, blunted the inhibitory effect of JWH-133 on lipopolysaccharideinduced nuclear factor-kappa B activation and M1 polarization. Altogether, these findings demonstrate that CB2 receptors display beneficial effects on alcohol-induced inflammation by regulating M1/M2 balance in Kupffer cells, thereby reducing hepatocyte steatosis via paracrine interactions between Kupffer cells and hepatocytes. These data identify CB2 agonists as potential therapeutic agents for the management of alcoholic liver disease.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice

et al. 2011

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“…It has been shown that nonalcoholic fatty liver disease, including hepatic steatosis, is closely related via enhanced inflammation to insulin resistance, metabolic syndrome, and cardiovascular disease [21][22][23][24] . Tabuchi et al 25) reported that ezetimibe inhibits the absorption of oxidized cholesterol and its deposition in the liver.…”

Section: Discussionmentioning

confidence: 99%

Ezetimibe Ameliorates Metabolic Disorders and Microalbuminuria in Patients with Hypercholesterolemia

Yagi

Akiyama

Aihara

et al. 2010

JAT

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Aim:Ezetimibe, an inhibitor of Niemann-Pick C1-like 1 protein, has been shown to reduce the intestinal absorption of cholesterol. We investigated whether it also has beneficial effects on metabolic disorder and/or renal insufficiency in patients with hypercholesterolemia. Methods: Ezetimibe was administered to 38 Japanese patients with hypercholesterolemia to obtain appropriate low-density lipoprotein cholesterol (LDL-chol) levels. Age-and sex-matched patients with hypercholesterolemia (n 38) were the controls. We evaluated the effects of ezetimibe before and 4 to 8 weeks after ezetimibe treatment. Results: Ezetimibe significantly decreased LDL-chol levels and metabolic syndrome-related factors, including body weight, waist circumference, blood pressure; homeostasis model assessment insulin resistance (HOMA-IR), and urinary albumin excretion, were significantly reduced. In addition, it decreased the level of high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-, the urinary excretion of 8-hydroxy-2'-deoxyguanosine, a parameter of oxidative stress, and increased the urinary excretion of nitrate and nitrite (NOx). In the controls we observed no such changes. Excepting the decrease in the serum TNF-level, the effects of ezetimibe were not correlated with decreased LDL-chol levels. Conclusion: Ezetimibe ameliorated the status of metabolic syndrome and microalbuminuria, reduced inflammation and oxidative stress, and increased nitric oxide bioavailability in a LDL-chol reductiondependent and -independent manner.

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“…Proinflammatory cytokines such as TNF-α and IL-6, which are derived from inflammatory cells, can interfere with insulin signalling in adipocytes, thereby promoting insulin resistance locally in the WAT as well as systemically [13,16]. For example, the inhibitor of κB kinase (IKK) and c-Jun N-terminal kinase (JNK) pathways that are activated by such macrophage-derived cytokines can directly impair insulin signalling in adipocytes and in other tissues, such as liver or muscle [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Lymphocytes in obesity-related adipose tissue inflammation

et al. 2012

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Inflammation in the white adipose tissue (WAT) is considered a major player in the development of insulin resistance. The role of macrophages accumulating in the WAT during obesity, promoting WAT inflammation and insulin resistance is well established. In contrast, less is known about the role of lymphocytes. Recent studies have implicated different lymphocyte subsets in WAT inflammation. For instance, cytotoxic CD8 + T cells infiltrating the WAT may contribute to the recruitment, differentiation and activation of macrophages. On the other hand, a differential role for CD4 + Th1 and CD4 + Th2 cells has been suggested.Levels of WAT regulatory T cells decrease during the course of obesity and may represent a crucial factor for the maintenance of insulin sensitivity. Moreover, activation of natural killer T cells, an innate-like T cell population, which recognises lipid antigens, promotes insulin resistance and WAT inflammation. Finally, B cells may infiltrate WAT very early in response to high-fat feeding and worsen glucose metabolism through modulation of T cells and the production of pathogenic antibodies. These interesting new findings however bear controversies and introduce novel, yet unanswered, questions. Here, we review and discuss the impact of the different lymphocyte subsets in obesityrelated WAT inflammation and attempt to identify the open questions to be answered by future studies.

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Macrophage TNF-α contributes to insulin resistance and hepatic steatosis in diet-induced obesity

Abstract: De Taeye BM, Novitskaya T, McGuinness OP, Gleaves L, Medda M, Covington JW, Vaughan DE. Macrophage TNF-␣ contributes to insulin resistance and hepatic steatosis in diet-induced obesity.

Cited by 185 publications

References 52 publications

Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice

Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice

Ezetimibe Ameliorates Metabolic Disorders and Microalbuminuria in Patients with Hypercholesterolemia

Lymphocytes in obesity-related adipose tissue inflammation

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