肥胖诱导的炎症与白色脂肪组织中环磷酸鸟苷信号转导的相互作用。
Interplay between Obesity-Induced Inflammation and cGMP Signaling in White Adipose Tissue.
机构信息
Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany; Bonn International Graduate School of Drug Sciences, University of Bonn, 53127 Bonn, Germany.
Institute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, Germany.
出版信息
Cell Rep. 2017 Jan 3;18(1):225-236. doi: 10.1016/j.celrep.2016.12.028.
Current worldwide figures suggest that obesity is pandemic. Understanding the underlying molecular mechanisms would help develop viable anti-obesity therapies. Here, we assess the influence of obesity-induced inflammation on white adipocyte cyclic guanosine monophosphate (cGMP) signaling, which is beneficial for adipocyte differentiation and thermogenesis. We find that murine gonadal and not inguinal fat is prone to obesity-induced inflammation. Correspondingly, the cGMP cascade is dysregulated in gonadal but not in inguinal fat of obese mice. Analysis of two independent human cohorts reveals a defective cGMP pathway only in visceral fat of obese subjects. Congruently, cGMP signaling is dysregulated in tumor necrosis factor α (TNF-α)-treated primary white adipocytes. TNF-α-mediated suppression of sGCβ is mediated via NF-κB, whereas PKG is repressed by JNK signaling. Additionally, TNF-α-activated JNK signaling suppresses PPARγ and aP2. Taken together, the intensity of obesity-induced inflammation dictates the amplitude of cGMP signaling dysregulation in white adipocytes through distinct pathways.
目前全球数据表明肥胖是普遍存在的。了解潜在的分子机制将有助于开发可行的抗肥胖疗法。在这里，我们评估肥胖引起的炎症对白色脂肪细胞环鸟苷酸单磷酸（cGMP）信号的影响，该信号有利于脂肪细胞分化和产热。我们发现，肥胖引起的炎症更容易发生在鼠的性腺脂肪而不是腹股沟脂肪中。相应地，肥胖小鼠的性腺脂肪而不是腹股沟脂肪中的 cGMP 级联反应失调。对两个独立的人类队列的分析表明，只有肥胖受试者的内脏脂肪中的 cGMP 途径存在缺陷。一致地，TNF-α 处理的原代白色脂肪细胞中的 cGMP 信号转导受到干扰。TNF-α 介导的 sGCβ 抑制是通过 NF-κB 介导的，而 PKG 则受到 JNK 信号的抑制。此外，TNF-α 激活的 JNK 信号抑制 PPARγ 和 aP2。综上所述，肥胖引起的炎症的强度通过不同的途径决定了白色脂肪细胞中 cGMP 信号转导失调的幅度。
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