Human adipocyte extracellular vesicles in reciprocal signaling between adipocytes and macrophages

Kranendonk, Mariëtte E.G.; Visseren, Frank L.J.; Balkom, Bas W. M. van; Hoen, Esther N. M. Nolte‐‘t; Herwaarden, Joost A. van; Jager, Wilco de; Bateman, Scott; Brenkman, Arjan B.; Verhaar, Marianne C.; Wauben, Marca H. M.; Kalkhoven, Eric

doi:10.1002/oby.20679

Cited by 169 publications

(170 citation statements)

References 42 publications

(60 reference statements)

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“…Once secreted, the majority of aP2 is detectable in the free form in circulation, but a small fraction persists in vesicles (data not shown). The vesicles bearing aP2 resemble exosomes in terms of size and marker expression, in agreement with previous reports ( 57 ). Our analysis of the density of the aP2-containing particles showed that they are at the high end of the density range reported for exosomes (1.19-1.21 g/ml) ( 58 ).…”

Section: Downloaded Fromsupporting

confidence: 92%

Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity

Ertunc

Sikkeland

Fenaroli

et al. 2015

Journal of Lipid Research

127

172

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Journal of Lipid Research Volume 56, 2015 423Adipose tissue is an endocrine organ whose products orchestrate the metabolic functions of various tissues, including brain, pancreas, and liver, to maintain systemic homeostasis. Adipocytes respond to metabolic and immune cues by mobilizing their fat stores through lipolysis and by secreting a variety of hormones and cytokines ( 1, 2 ). Such signals converge on target tissues, for example on liver to regulate glucose production, and on ␤ cells to modulate insulin production. A critical molecule for the integration of adipocyte biology with systemic metabolic regulation is aP2 [fatty acid binding protein (FABP) 4], a lipid binding protein that is upregulated during differentiation of adipocytes and upon macrophage activation ( 3, 4 ). Since its identifi cation, aP2 has been studied primarily for its intracellular functions in lipid metabolism and infl ammation ( 3,4 ). Genetic deletion models demonstrated that this FABP plays a critical role in the pathogenesis of several chronic metabolic diseases, including diabetes, atherosclerosis, and fatty liver. Mice defi cient in aP2 or aP2 and the related protein FABP5/mal1 together have improved adipose and liver function, increased insulin sensitivity, and reduced fatty liver and cardiovascular disease in the context of high-fat diet and genetic mouse models of obesity and atherosclerosis ( 5-12 ). The link between aP2 and metabolic disease is also supported by genetic association studies in multiple populations demonstrating metabolic and cardiovascular benefi ts in individuals carrying a rare haploinsuffi ciency mutation in the aP2 locus, validating the relevance of this pathway in human disease ( 13,14 ).

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Section: Downloaded Fromsupporting

confidence: 92%

Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity

Ertunc

Sikkeland

Fenaroli

et al. 2015

Journal of Lipid Research

127

172

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“…Exosomes isolated from adipose tissue mediated adipose tissue inflammation in a murine model [19]. Exosomes secreted by differentiated human adipocytes and human adipose tissue explants had immunomodulatory effects on macrophages, and exosome-stimulated macrophages induced insulin resistance in adipocytes [20]. However, no data are available on the signalling molecules carried by exosomes during communication between adipocytes and macrophages.…”

Section: Introductionmentioning

confidence: 99%

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

Song

Han

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Adipocyte-derived exosomes (ADEs) stimulate the activation of macrophages and contribute to the development of insulin resistance. Sonic Hedgehog (Shh) is an exosome-carrying protein and stimulates macrophages to secrete inflammatory cytokines. However, the impact of ADEs carrying Shh on the pro-inflammatory activation of macrophages and consequently, adipocyte insulin resistance is unclear. Methods: 3T3-L1 adipocytes were cultured with high glucose and insulin to imitate the pathogeny of insulin resistance. ADEs were isolated from conditioned media of 3T3-L1 adipocytes via differential ultracentrifugation. We explored the role of ADEs carrying Shh in the polarization of macrophages by flow cytometry. Western blot and electrophoretic mobility shift assay (EMSA) were performed to determine the activation of Shh-mediated signalling pathways. The effects of ADE-treated macrophages on adipocyte insulin signalling were studied by Western blot. Results: We found that circulating Shh-positive exosomes were increased in type 2 diabetes patients. High glucose and insulin increased the secretion of Shh-positive ADEs. The ADEs carrying Shh induced pro-inflammatory or M1 polarization of bone marrow-derived macrophages (BMDM) and RAW 264.7 macrophages. Inhibitors of Ptch and PI3K blocked the M1 polarization induced by ADEs, which suggests that ADEs carrying Shh mediated M1 macrophage polarization through the Ptch/PI3K signalling pathway. ADE-treated RAW 264.7 macrophages were subsequently used to assess the effect on insulin signalling in adipocytes. Using a co-culture assay, we showed that both ADE-treated macrophages and exosomes from these macrophages could decrease the expression of insulin-resistant substrate-1 (IRS-1) and hormone-sensitive lipase (HSL) in adipocytes. Inhibitors of Ptch and PI3K blocked the down-regulation of IRS-1 and HSL induced by ADE-treated macrophages. Conclusion: Together, these data indicate that ADEs carrying Shh induce the M1 polarization of macrophages, which contributes to insulin resistance in adipocytes through the Ptch/PI3K pathway.

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“…8,9 Mouse visceral adipose tissue EVs mediate activation of macrophage-induced insulin resistance. 10 Cultures of murine pre-adipocytes have also been shown to release EVs and these EVs stimulate fatty acid-oxidation dependent migration of melanoma cells.…”

Section: Introductionmentioning

confidence: 99%

The isolation of morphologically intact and biologically active extracellular vesicles from the secretome of cancer-associated adipose tissue

Jeurissen

Vergauwen

Deun

et al. 2017

Cell Adhesion & Migration

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Breast cancer cells closely interact with different cell types of the surrounding adipose tissue to favor invasive growth and metastasis. Extracellular vesicles (EVs) are nanometer-sized vesicles secreted by different cell types that shuttle proteins and nucleic acids to establish cell-cell communication. To study the role of EVs released by cancer-associated adipose tissue in breast cancer progression and metastasis a standardized EV isolation protocol that obtains pure EVs and maintains their functional characteristics is required. We implemented differential ultracentrifugation as a pre-enrichment step followed by OptiPrep density gradient centrifugation (dUC-ODG) to isolate EVs from the conditioned medium of cancer-associated adipose tissue. A combination of immune-electron microscopy, nanoparticle tracking analysis (NTA) and Western blot analysis identified EVs that are enriched in flotillin-1, CD9 and CD63, and sized between 20 and 200 nm with a density of 1.076-1.125 g/ml. The lack of protein aggregates and cell organelle proteins confirmed the purity of the EV preparations. Next, we evaluated whether dUC-ODG isolated EVs are functionally active. ZR75.1 breast cancer cells treated with cancer-associated adipose tissue-secreted EVs from breast cancer patients showed an increased phosphorylation of CREB. MCF-7 breast cancer cells treated with adipose tissue-derived EVs exhibited a stronger propensity to form cellular aggregates. In conclusion, dUC-ODG purifies EVs from conditioned medium of cancer-associated adipose tissue, and these EVs are morphologically intact and biologically active.

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Human adipocyte extracellular vesicles in reciprocal signaling between adipocytes and macrophages

Cited by 169 publications

References 42 publications

Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity

Secretion of fatty acid binding protein aP2 from adipocytes through a nonclassical pathway in response to adipocyte lipase activity

Adipocyte-Derived Exosomes Carrying Sonic Hedgehog Mediate M1 Macrophage Polarization-Induced Insulin Resistance via Ptch and PI3K Pathways

The isolation of morphologically intact and biologically active extracellular vesicles from the secretome of cancer-associated adipose tissue

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