Division of Basic Biomedical Sciences Sanford School of Medicine of the University of South Dakota Vermillion SD.
J Am Heart Assoc. 2021 Jul 20;10(14):e020667. doi: 10.1161/JAHA.120.020667. Epub 2021 Jul 14.
Background Hypothalamic leptin-mediated signaling contributes to the exaggerated sympatho-excitation and increased blood pressure in obesity-associated hypertension. The aim of the study was to investigate the roles of energy-sensing enzyme sirtuin1 (Sirt1) and forkhead box protein O1 (FoxO1) on the hypothalamic leptin-mediated high sympathetic nerve activity and inflammation in obesity. Methods and Results Sprague Dawley rats were fed with high-fat diet (HFD) for 12 weeks. In vivo, the potential of Srit1 and FoxO1 in the sympathetic effects of leptin was investigated via siRNA injection to knockdown Sirt1 or FoxO1 gene in the arcuate nucleus (ARCN) of hypothalamus in rats. In vitro, the effects of Sirt1 or FoxO1 on leptin-mediated inflammation were observed in proopiomelanocortin (POMC) and microglial cells. Knockdown Sirt1 by siRNA significantly reduced the renal sympathetic nerve activity (RSNA) and blood pressure responses to leptin injection in the ARCN in the HFD rats. Conversely, knockdown FoxO1 significantly enhanced the RSNA and blood pressure responses to leptin injection in the HFD rats. Knockdown Sirt1 reduced the levels of pro-inflammatory cytokines interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), C1q/TNF-related protein-1 (CTRP1), and immune cell infiltration in the ARCN in the HFD rats. Knockdown FoxO1 significantly increased the level of IL-6 in the ARCN of HFD rats. In cultured hypothalamic POMC and microglial cells, knockdown Sirt1 significantly reduced leptin-induced IL-6 expression, affected the levels of AMP-activated protein kinase (AMPK) and serine/threonine-specific protein kinase (Akt). Knockdown FoxO1 significantly increased leptin-induced IL-6 in both POMC cells and microglial cells. Conclusions These data suggest that both Sirt1 and FoxO1 are the key modulators of leptin signaling in the hypothalamus contributed to the over sympathetic activation and inflammation in obesity.
下丘脑瘦素介导的信号转导有助于肥胖相关高血压中交感神经兴奋的过度增强和血压升高。本研究旨在探讨能量感应酶 Sirtuin1（Sirt1）和叉头框蛋白 O1（FoxO1）在肥胖引起的下丘脑瘦素介导的高交感神经活性和炎症中的作用。
Sprague Dawley 大鼠给予高脂肪饮食（HFD）喂养 12 周。在体内，通过 siRNA 注射将 Sirt1 或 FoxO1 基因敲低到下丘脑弓状核（ARCN）中，研究 Sirt1 和 FoxO1 在瘦素的交感效应中的潜在作用。在体外，观察 Sirt1 或 FoxO1 对瘦素介导的炎症的影响在 proopiomelanocortin（POMC）和小胶质细胞中。siRNA 敲低 Sirt1 可显著降低 HFD 大鼠 ARCN 中瘦素注射引起的肾交感神经活性（RSNA）和血压反应。相反，敲低 FoxO1 可显著增强 HFD 大鼠瘦素注射引起的 RSNA 和血压反应。siRNA 敲低 Sirt1 可降低 HFD 大鼠 ARCN 中促炎细胞因子白细胞介素 6（IL-6）、肿瘤坏死因子-α（TNF-α）、白细胞介素 1β（IL-1β）、C1q/TNF 相关蛋白 1（CTRP1）和免疫细胞浸润的水平。敲低 FoxO1 可显著增加 HFD 大鼠 ARCN 中的 IL-6 水平。在培养的下丘脑 POMC 和小胶质细胞中，siRNA 敲低 Sirt1 可显著降低瘦素诱导的 IL-6 表达，影响 AMP 激活蛋白激酶（AMPK）和丝氨酸/苏氨酸特异性蛋白激酶（Akt）的水平。敲低 FoxO1 可显著增加 POMC 细胞和小胶质细胞中瘦素诱导的 IL-6。
这些数据表明，Sirt1 和 FoxO1 都是下丘脑瘦素信号转导的关键调节因子，有助于肥胖引起的交感神经过度激活和炎症。
