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Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance.

ABSTRACT: Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDCs), contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we use CD64 to distinguish ATM and ATDC, and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80+CD11b+ cells overlaps with other leukocytes and that CD45+CD64+ is specific for ATM. The expression of core dendritic cell genes was enriched in CD11c+CD64- cells (ATDC), whereas core macrophage genes were enriched in CD45+CD64+ cells (ATM). CD11c+CD64- ATDCs expressed MHC class II and costimulatory receptors, and had similar capacity to stimulate CD4+ T cell proliferation as ATMs. ATDCs were predominantly CD11b+ conventional dendritic cells and made up the bulk of CD11c+ cells in adipose tissue with moderate high-fat diet exposure. Mixed chimeric experiments with Ccr2-/- mice demonstrated that high-fat diet-induced ATM accumulation from monocytes was dependent on CCR2, whereas ATDC accumulation was less CCR2 dependent. ATDC accumulation during obesity was attenuated in Ccr7-/- mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45+CD64+ ATM and CD45+CD64-CD11c+ ATDCs were identified in human obese adipose tissue and ATDCs were increased in s.c. adipose tissue compared with omental adipose tissue. These results support a revised strategy for unambiguous delineation of ATM and ATDC, and suggest that ATDCs are independent contributors to adipose tissue inflammation during obesity.

SUBMITTER: Cho KW

PROVIDER: S-EPMC5555636 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance.

Cho Kae Won KW Zamarron Brian F BF Muir Lindsey A LA Singer Kanakadurga K Porsche Cara E CE DelProposto Jennifer B JB Geletka Lynn L Meyer Kevin A KA O'Rourke Robert W RW Lumeng Carey N CN

Journal of immunology (Baltimore, Md. : 1950) 20160928 9

Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDCs), contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we use CD64 to distinguish ATM and ATDC, and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immun ...[more]

PMID: 27683748

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Project description:AbatractObesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE-RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE-/-) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE-/- mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE-/- mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE-/--HFD mice. RAGE-/- mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE-/- mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.

Dataset Information

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance.

Publications

Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance.

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