Alterations in Mouse Hypothalamic Adipokine Gene Expression and Leptin Signaling following Chronic Spinal Cord Injury and with Advanced Age
Alterations in Mouse Hypothalamic Adipokine Gene Expression and Leptin Signaling following Chronic Spinal Cord Injury and with Advanced Age
复制标题
DOI：
10.1371/journal.pone.0041073
复制
发表时间：
2012-07-16
期刊：
影响因子：
3.7
通讯作者：
Bethea, John R.
中科院分区：
文献类型：
--
作者：
Bigford, Gregory E.;Bracchi-Ricard, Valerie C.;Bethea, John R.
慢性脊髓损伤(SCI)导致几种心血管疾病(CVD)危险因素和相关衰老特征的加速发展，但其被激活的分子机制尚未被探索。脂肪因子和瘦素信号在能量代谢的神经内分泌调节中发挥关键作用，目前与心血管疾病相关的中枢炎症过程有关。在这里，我们研究了下丘脑脂肪因子基因的表达和瘦素信号在慢性脊髓损伤和高龄患者中的反应。我们发现，在慢性脊髓损伤和高龄后，空腹诱导脂肪因子(FIAF)、抵抗素(Rstn)、长型瘦素受体(LepRb)和细胞因子3抑制因子(SOCS3)基因的表达发生了显著变化。随着慢性脊髓损伤和增龄，LepRb和JAK2/STAT3信号转导显著降低，瘦素信号转导抑制物SOCS3显著升高。此外，我们还研究了内质网(ER)应激和解偶联蛋白反应(UPR)的激活作为瘦素抵抗的生物学标志。我们观察到ER应激/UPR蛋白IRE1、PERK和eIF2α的激活，表明在慢性脊髓损伤和高龄患者中存在瘦素抵抗。这些发现提供了脂肪因子介导的炎症反应和瘦素抵抗导致脊髓损伤后和高龄患者神经内分泌功能障碍和心血管疾病风险的证据。了解脊髓损伤和年龄相关心血管疾病的潜在机制可能有助于指导具体的治疗干预。
Chronic spinal cord injury (SCI) results in an accelerated trajectory of several cardiovascular disease (CVD) risk factors and related aging characteristics, however the molecular mechanisms that are activated have not been explored. Adipokines and leptin signaling are known to play a critical role in neuro-endocrine regulation of energy metabolism, and are now implicated in central inflammatory processes associated with CVD. Here, we examine hypothalamic adipokine gene expression and leptin signaling in response to chronic spinal cord injury and with advanced age. We demonstrate significant changes in fasting-induced adipose factor (FIAF), resistin (Rstn), long-form leptin receptor (LepRb) and suppressor of cytokine-3 (SOCS3) gene expression following chronic SCI and with advanced age. LepRb and Jak2/stat3 signaling is significantly decreased and the leptin signaling inhibitor SOCS3 is significantly elevated with chronic SCI and advanced age. In addition, we investigate endoplasmic reticulum (ER) stress and activation of the uncoupled protein response (UPR) as a biological hallmark of leptin resistance. We observe the activation of the ER stress/UPR proteins IRE1, PERK, and eIF2alpha, demonstrating leptin resistance in chronic SCI and with advanced age. These findings provide evidence for adipokine-mediated inflammatory responses and leptin resistance as contributing to neuro-endocrine dysfunction and CVD risk following SCI and with advanced age. Understanding the underlying mechanisms contributing to SCI and age related CVD may provide insight that will help direct specific therapeutic interventions.