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髓样过氧化物酶-1 单倍体不足通过影响脂肪组织巨噬细胞浸润减少高脂肪饮食诱导的胰岛素抵抗。

Myeloid heme oxygenase-1 haploinsufficiency reduces high fat diet-induced insulin resistance by affecting adipose macrophage infiltration in mice.

机构信息

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.

出版信息

PLoS One. 2012;7(6):e38626. doi: 10.1371/journal.pone.0038626. Epub 2012 Jun 21.

DOI:10.1371/journal.pone.0038626
PMID:22761690
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3382977/
Abstract

Increased adipose tissue macrophages contribute to obesity-induced metabolic syndrome. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with potent anti-inflammatory and proangiogenic activities in macrophages. However, the role of macrophage HO-1 on obesity-induced adipose inflammation and metabolic syndrome remains unclear. Here we show that high-fat diet (HFD) feeding in C57BL/6J mice induced HO-1 expression in the visceral adipose tissue, particularly the stromal vascular fraction. When the irradiated C57BL/6J mice reconstituted with wild-type or HO-1(+/-) bone marrow were fed with HFD for over 24 weeks, the HO-1(+/-) chimeras were protected from HFD-induced insulin resistance and this was associated with reduced adipose macrophage infiltration and angiogenesis, suggesting that HO-1 affects myeloid cell migration toward adipose tissue during obesity. In vivo and in vitro migration assays revealed that HO-1(+/-) macrophages exhibited an impaired migration response. Chemoattractant-induced phosphorylation of p38 and focal adhesion kinase (FAK) declined faster in HO-1(+/-) macrophages. Further experiments demonstrated that carbon monoxide and bilirubin, the byproducts derived from heme degradation by HO-1, enhanced macrophage migration by increasing phosphorylation of p38 and FAK, respectively. These data disclose a novel role of hematopoietic cell HO-1 in promoting adipose macrophage infiltration and the development of insulin resistance during obesity.

摘要

脂肪组织中巨噬细胞的增加导致肥胖引起的代谢综合征。血红素加氧酶-1（HO-1）是一种应激诱导酶，在巨噬细胞中具有强大的抗炎和促血管生成作用。然而，巨噬细胞 HO-1 对肥胖引起的脂肪炎症和代谢综合征的作用尚不清楚。在这里，我们发现高脂肪饮食（HFD）喂养 C57BL/6J 小鼠诱导内脏脂肪组织中 HO-1 的表达，特别是基质血管部分。当用 HFD 喂养超过 24 周的辐照 C57BL/6J 小鼠用野生型或 HO-1(+/-)骨髓重建时，HO-1(+/-)嵌合体免受 HFD 诱导的胰岛素抵抗，这与脂肪巨噬细胞浸润和血管生成减少有关，表明 HO-1 影响肥胖期间骨髓细胞向脂肪组织的迁移。体内和体外迁移实验表明，HO-1(+/-)巨噬细胞表现出受损的迁移反应。HO-1(+/-)巨噬细胞中趋化因子诱导的 p38 和 focal adhesion kinase (FAK) 的磷酸化更快下降。进一步的实验表明，CO 和胆红素，HO-1 降解血红素的副产物，分别通过增加 p38 和 FAK 的磷酸化来增强巨噬细胞的迁移。这些数据揭示了造血细胞 HO-1 在促进肥胖期间脂肪巨噬细胞浸润和胰岛素抵抗发展中的新作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/8dd84d99804a/pone.0038626.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/1000a28f6502/pone.0038626.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/7525715dcc0c/pone.0038626.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/1725c9e0f83f/pone.0038626.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/d89178a11459/pone.0038626.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/a5b228e3e15c/pone.0038626.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/fd75882be439/pone.0038626.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/35fcecafe41b/pone.0038626.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/5c66734ea972/pone.0038626.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/8dd84d99804a/pone.0038626.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/1000a28f6502/pone.0038626.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/7525715dcc0c/pone.0038626.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/1725c9e0f83f/pone.0038626.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/d89178a11459/pone.0038626.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/a5b228e3e15c/pone.0038626.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/fd75882be439/pone.0038626.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/35fcecafe41b/pone.0038626.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/5c66734ea972/pone.0038626.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7945/3382977/8dd84d99804a/pone.0038626.g009.jpg

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