Obesogenic diet disrupts tissue-specific mitochondrial gene signatures in the artery and capillary endothelium.
Obesogenic diet disrupts tissue-specific mitochondrial gene signatures in the artery and capillary endothelium.
复制标题
致肥胖饮食会破坏动脉和毛细血管内皮细胞中组织特异性线粒体基因特征。
DOI：
10.1152/physiolgenomics.00109.2023
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发表时间：
2024
影响因子：
4.6
通讯作者：
Isakson,BrantE
中科院分区：
文献类型：
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作者：
Dunaway,LukeS;Luse,MelissaA;Nyshadham,Shruthi;Bulut,Gamze;Alencar,GabrielF;Chavkin,NicholasW;Cortese-Krott,Miriam;Hirschi,KarenK;Isakson,BrantE
内皮细胞（EC）适应其驻留组织的独特需求和代谢扰动，例如肥胖。我们试图了解肥胖如何影响 EC 代谢表型，特别是线粒体基因表达。我们研究了肠系膜和脂肪内皮，因为这些血管床在脂质稳态中具有不同的作用。最初，我们对正常饮食（NC）或高脂饮食（HFD）后的小鼠脂肪和肠系膜脉管系统的 EC 进行了批量 RNA 测序，发现与 NC 和 HFD 小鼠的肠系膜 EC 相比，脂肪 EC 中的线粒体基因表达更高。接下来，我们进行了单细胞 RNA 测序，并将 EC 分类为动脉、毛细血管、静脉或淋巴管。我们发现，在动脉和毛细血管内皮细胞的NC条件下，与肠系膜相比，线粒体基因在脂肪中富集。 HFD 后，这些基因在脂肪 EC 中减少，变得像肠系膜 EC。转录因子分析表明，过氧化物酶体增殖物激活受体-γ (PPAR-γ) 在 NC 脂肪动脉和毛细血管 EC 中具有高度特异性。这些发现在人类内脏脂肪的单核 RNA 测序数据中得到了概括。这些发现的总和表明，肠系膜和脂肪动脉 EC 对脂质的代谢不同，并且由于脂肪动脉和毛细血管 EC 中 PPAR-γ 的下调，血管床的转录表型在肥胖中趋于一致。新的和值得注意的对脂肪和肠系膜的内皮细胞使用大量和单细胞 RNA 测序，我们发现致肥胖饮食会导致脂肪减少内皮氧化磷酸化基因表达，导致肠系膜和脂肪内皮细胞表型趋同。此外，我们发现 PPAR-γ 驱动这种表型转变的证据。根据体重指数分离的人体数据集的挖掘支持了这些发现。这些数据指出了肥胖引起内皮功能障碍的新机制。
Endothelial cells (ECs) adapt to the unique needs of their resident tissue and metabolic perturbations, such as obesity. We sought to understand how obesity affects EC metabolic phenotypes, specifically mitochondrial gene expression. We investigated the mesenteric and adipose endothelium because these vascular beds have distinct roles in lipid homeostasis. Initially, we performed bulk RNA sequencing on ECs from mouse adipose and mesenteric vasculatures after a normal chow (NC) diet or high-fat diet (HFD) and found higher mitochondrial gene expression in adipose ECs compared with mesenteric ECs in both NC and HFD mice. Next, we performed single-cell RNA sequencing and categorized ECs as arterial, capillary, venous, or lymphatic. We found mitochondrial genes to be enriched in adipose compared with mesentery under NC conditions in artery and capillary ECs. After HFD, these genes were decreased in adipose ECs, becoming like mesenteric ECs. Transcription factor analysis revealed that peroxisome proliferator-activated receptor-γ (PPAR-γ) had high specificity in NC adipose artery and capillary ECs. These findings were recapitulated in single-nuclei RNA-sequencing data from human visceral adipose. The sum of these findings suggests that mesenteric and adipose arterial ECs metabolize lipids differently, and the transcriptional phenotype of the vascular beds converges in obesity due to downregulation of PPAR-γ in adipose artery and capillary ECs.NEW & NOTEWORTHYUsing bulk and single-cell RNA sequencing on endothelial cells from adipose and mesentery, we found that an obesogenic diet induces a reduction in adipose endothelial oxidative phosphorylation gene expression, resulting in a phenotypic convergence of mesenteric and adipose endothelial cells. Furthermore, we found evidence that PPAR-γ drives this phenotypic shift. Mining of human data sets segregated based on body mass index supported these findings. These data point to novel mechanisms by which obesity induces endothelial dysfunction.