Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome
Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome
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DOI：
10.1152/ajpendo.91014.2008
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发表时间：
2009-07-01
影响因子：
5.1
通讯作者：
Samad, Fahumiya
中科院分区：
文献类型：
--
作者：
Yang, Guang;Badeanlou, Leylla;Samad, Fahumiya
Yang G，Badeanlou L，Bielawski J，Roberts AJ，Hannun YA，Samad F.神经酰胺生物合成在体重调节、能量代谢和代谢综合征中的中心作用。Am J Physiol Endocrinol Metab 297：E211-E224，2009.首次发表于2009年5月12日; doi：10.1152/ajpendo.91014.2008。虽然肥胖与代谢综合征的多种特征（胰岛素抵抗、瘦素抵抗、肝脂肪变性、慢性炎症等）相关，促进这些条件的分子变化还没有完全理解。在这里，我们测试的假设，神经酰胺的生物合成增加有助于肥胖和代谢综合征的发病机制。对遗传性肥胖（ob/ob）和高脂饮食诱导的肥胖（DIO）小鼠用多球壳菌素（一种从头神经酰胺合成的抑制剂）长期治疗8周，降低了循环神经酰胺。神经酰胺减少与体重减轻、代谢和能量消耗增强、肝脏脂肪变性减少以及通过增强肝脏和肌肉中的胰岛素信号传导改善葡萄糖止血相关。从头神经酰胺生物合成的抑制降低了脂肪细胞因子信号传导抑制因子-3（SOCS-3）的表达，并诱导了脂肪解偶联蛋白-3（UCP 3）。此外，在培养的脂肪细胞中，神经酰胺直接诱导SOCS-3和抑制UCP 3 mRNA，表明神经酰胺在调节代谢和能量消耗中的直接作用。从头神经酰胺合成的抑制对脂肪肿瘤坏死因子-α（TNF-α）表达没有影响，但显著降低了脂肪纤溶酶原激活物抑制剂-1（派-1）和单核细胞趋化蛋白-1（MCP-1）。这项研究强调了神经酰胺生物合成在体重调节、能量消耗和代谢综合征中的新作用。
Yang G, Badeanlou L, Bielawski J, Roberts AJ, Hannun YA, Samad F. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am J Physiol Endocrinol Metab 297: E211-E224, 2009. First published May 12, 2009; doi: 10.1152/ajpendo.91014.2008.-Although obesity is associated with multiple features of the metabolic syndrome (insulin resistance, leptin resistance, hepatic steatosis, chronic inflammation, etc.), the molecular changes that promote these conditions are not completely understood. Here, we tested the hypothesis that elevated ceramide biosynthesis contributes to the pathogenesis of obesity and the metabolic syndrome. Chronic treatment for 8 wk of genetically obese (ob/ob), and, high-fat diet-induced obese (DIO) mice with myriocin, an inhibitor of de novo ceramide synthesis, decreased circulating ceramides. Decreased ceramide was associated with reduced weight, enhanced metabolism and energy expenditure, decreased hepatic steatosis, and improved glucose hemostasis via enhancement of insulin signaling in the liver and muscle. Inhibition of de novo ceramide biosynthesis decreased adipose expression of suppressor of cytokine signaling-3 (SOCS-3) and induced adipose uncoupling protein-3 (UCP3). Moreover, ceramide directly induced SOCS-3 and inhibited UCP3 mRNA in cultured adipocytes suggesting a direct role for ceramide in regulation of metabolism and energy expenditure. Inhibition of de novo ceramide synthesis had no effect on adipose tumor necrosis factor-alpha(TNF-alpha) expression but dramatically reduced adipose plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattactant protein-1 (MCP-1). This study highlights a novel role for ceramide biosynthesis in body weight regulation, energy expenditure, and the metabolic syndrome.