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Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release
Yoshinari Obata, … , Norikazu Maeda, Iichiro Shimomura
Yoshinari Obata, … , Norikazu Maeda, Iichiro Shimomura
Published April 19, 2018
Citation Information: JCI Insight. 2018;3(8):e99680. https://doi.org/10.1172/jci.insight.99680.
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Research Article Cell biology Metabolism

Adiponectin/T-cadherin system enhances exosome biogenesis and decreases cellular ceramides by exosomal release

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Abstract

Adiponectin, an adipocyte-derived circulating protein, accumulates in vasculature, heart, and skeletal muscles through interaction with a unique glycosylphosphatidylinositol-anchored cadherin, T-cadherin. Recent studies have demonstrated that such accumulation is essential for adiponectin-mediated cardiovascular protection. Here, we demonstrate that the adiponectin/T-cadherin system enhances exosome biogenesis and secretion, leading to the decrease of cellular ceramides. Adiponectin accumulated inside multivesicular bodies, the site of exosome generation, in cultured cells and in vivo aorta, and also in exosomes in conditioned media and in blood, together with T-cadherin. The systemic level of exosomes in blood was significantly affected by adiponectin or T-cadherin in vivo. Adiponectin increased exosome biogenesis from the cells, dependently on T-cadherin, but not on AdipoR1 or AdipoR2. Such enhancement of exosome release accompanied the reduction of cellular ceramides through ceramide efflux in exosomes. Consistently, the ceramide reduction by adiponectin was found in aortas of WT mice treated with angiotensin II, but not in T-cadherin–knockout mice. Our findings provide insights into adiponectin/T-cadherin–mediated organ protection through exosome biogenesis and secretion.

Authors

Yoshinari Obata, Shunbun Kita, Yoshihisa Koyama, Shiro Fukuda, Hiroaki Takeda, Masatomo Takahashi, Yuya Fujishima, Hirofumi Nagao, Shigeki Masuda, Yoshimitsu Tanaka, Yuto Nakamura, Hitoshi Nishizawa, Tohru Funahashi, Barbara Ranscht, Yoshihiro Izumi, Takeshi Bamba, Eiichiro Fukusaki, Rikinari Hanayama, Shoichi Shimada, Norikazu Maeda, Iichiro Shimomura

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Figure 1

Intraluminal accumulation of adiponectin in vesicles of multivesicular bodies (MVBs) in T-cadherin–expressing endothelial cells.

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Intraluminal accumulation of adiponectin in vesicles of multivesicular b...
(A) Western blots of total cell lysates. F2 cells with T-cadherin depletion (by RNAi) or stably overexpressed T-cadherin (F2T cells) were treated with medium containing 5% adiponectin-knockout (AKO) mouse serum, or WT mouse serum. APN, adiponectin; T-cad, T-cadherin; HMW, high molecular weight; MMW, middle molecular weight; LMW, low molecular weight. Representative results of 5 experiments with similar findings. (B and C) Confocal immunofluorescence micrographs of F2T cells. Cells cultured with AKO mouse serum or WT mouse serum were stained with anti-adiponectin, anti–T-cadherin, anti-EEA1 (early endosome), or anti-CD63 (MVB) antibodies. Cell nuclei were counterstained with DAPI. Scale bars: 20 μm. Higher magnifications of the boxed areas are shown in the right panels. Scale bars: 5 μm. (D) Immunoelectron micrographs using the pre-embedding immunoperoxidase technique for adiponectin in F2T cells cultured with WT mouse serum or AKO mouse serum. Right panels are higher magnifications of the regions outlined in the left panels. Scale bars: 5 μm (left panels) and 1 μm (right panels). Arrowhead, MVB; N, nucleus; Mt, mitochondria; ER, endoplasmic reticulum. (E) Immunoelectron micrographs using the pre-embedding immunogold labeling technique for adiponectin in F2T cells cultured with WT mouse serum or AKO mouse serum. Scale bar: 0.5 μm. (F–M) Immunoelectron micrographs using the pre-embedding immunoperoxidase technique for adiponectin in aorta of male WT mouse or AKO mouse. G, J, and M are higher magnifications of the regions outlined in F, I, and L, respectively. (H) Endosomes in panel G are outlined for easier identification. (K) A limiting membrane and intraluminal structures in panel J are outlined for easier identification. Scale bars: 500 nm (F, I, and L) and 200 nm (G, H, J, K, and M). Arrow, MVB; N, nucleus; L, lumen; BL, basal lamina; IEL, internal elastic lamina.

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