PDGFRβ Regulates Adipose Tissue Expansion and Glucose Metabolism via Vascular Remodeling in Diet-Induced Obesity
PDGFRβ Regulates Adipose Tissue Expansion and Glucose Metabolism via Vascular Remodeling in Diet-Induced Obesity
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DOI：
10.2337/db16-0881
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发表时间：
2017-04-01
期刊：
影响因子：
7.7
通讯作者：
Sasaoka, Toshiyasu
中科院分区：
文献类型：
--
作者：
Onogi, Yasuhiro;Wada, Tsutomu;Sasaoka, Toshiyasu
血小板衍生生长因子（PDGF）是血管生成的关键因子，然而，其在成人肥胖中的作用仍不清楚。为了阐明其病理生理作用，我们研究了PDGF受体β（PDGFR β）在脂肪组织扩张和葡萄糖代谢中的意义。正常小鼠附睾白色脂肪组织（eWAT）中的成熟血管被周细胞紧紧包裹。饮食诱导的肥胖小鼠的eWAT中，血管周细胞解吸和随后的内皮细胞增殖显著增加。流式细胞术和脂肪组织培养的分析表明，PDGF-B以浓度依赖性方式引起周细胞从血管中脱离。M1-巨噬细胞是肥胖脂肪组织中表达PDGF-β的主要细胞类型。相比之下，在他莫昔芬诱导的条件性Pdgfrb基因敲除小鼠中，周细胞脱离减弱，eWAT内的血管减少，脂肪细胞大小和慢性炎症减少。此外，Pdgfrb基因敲除小鼠表现出增强的能量消耗。因此，饮食诱导的肥胖症和相关的葡萄糖代谢恶化的野生型小鼠中不存在的Pdgfrb基因敲除小鼠。因此，PDGF-B-PDGFRb信号传导在脂肪组织新血管形成的发展中起重要作用，并且似乎是预防肥胖和2型糖尿病的基本靶点。
Platelet-derived growth factor (PDGF) is a key factor in angiogenesis; however, its role in adult obesity remains unclear. In order to clarify its pathophysiological role, we investigated the significance of PDGF receptor beta (PDGFR beta) in adipose tissue expansion and glucose metabolism. Mature vessels in the epididymal white adipose tissue (eWAT) were tightly wrapped with pericytes in normal mice. Pericyte desorption from vessels and the subsequent proliferation of endothelial cells were markedly increased in the eWAT of diet-induced obese mice. Analyses with flow cytometry and adipose tissue cultures indicated that PDGF-B caused the detachment of pericytes from vessels in a concentrationdependent manner. M1-macrophages were a major type of cells expressing PDGF-beta in obese adipose tissue. In contrast, pericyte detachment was attenuated and vascularity within eWAT was reduced in tamoxifen-inducible conditional Pdgfrb-knockout mice with decreases in adipocyte size and chronic inflammation. Furthermore, Pdgfrb-knockout mice showed enhanced energy expenditure. Consequently, diet-induced obesity and the associated deterioration of glucose metabolism in wild-type mice were absent in Pdgfrb-knockout mice. Therefore, PDGF-B-PDGFRb signaling plays a significant role in the development of adipose tissue neovascularization and appears to be a fundamental target for the prevention of obesity and type 2 diabetes.