Tumor necrosis factor-α contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes
Tumor necrosis factor-α contributes to obesity-related hyperleptinemia by regulating leptin release from adipocytes
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DOI：
10.1172/jci119824
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发表时间：
1997-12-01
影响因子：
15.9
通讯作者：
Hotamisligil, GS
中科院分区：
文献类型：
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作者：
Kirchgessner, TG;Uysal, K;Hotamisligil, GS
细胞因子，特别是肿瘤坏死因子-α（TNF-α），对能量代谢和食欲有显着的影响，但其作用机制在很大程度上是未知的。在这里，我们研究了TNF-α是否调节瘦素的产生，瘦素是最近发现的脂肪特异性能量平衡激素，在培养的脂肪细胞和小鼠中。TNF-α处理3 T3-L1脂肪细胞导致培养基中瘦素积累的快速刺激，在6 h时效果最大。这种刺激对蛋白质合成抑制剂放线菌酮不敏感，但被分泌抑制剂布雷菲德菌素A完全抑制，表明存在翻译后效应。用TNF-α治疗小鼠也引起了血浆瘦素水平的类似增加。最后，与肥胖野生型动物相比，在TNF-α缺陷的肥胖小鼠中，循环瘦素水平显著降低，而脂肪组织瘦素水平升高。这些数据提供了证据表明，TNF-α可以直接作用于脂肪细胞，以调节预先形成的瘦素库的释放。此外，他们表明，肥胖症中发生的TNF-α脂肪组织表达的升高可能有助于肥胖相关的高瘦素血症。
Cytokines, in particular tumor necrosis factor-alpha (TNF-alpha), have significant effects on energy metabolism and appetite although their mechanisms of action are largely unknown. Here, we examined whether TNF-alpha modulates the production of leptin, the recently identified fat-specific energy balance hormone, in cultured adipocytes and in mice. TNF-alpha treatment of 3T3-L1 adipocytes resulted in rapid stimulation of leptin accumulation in the media, with a maximum effect at 6 h, This stimulation was insensitive to cycloheximide, a protein synthesis inhibitor, but was completely inhibited by the secretion inhibitor brefeldin A, indicating a posttranslational effect. Treatment of mice with TNF-alpha also caused a similar increase in plasma leptin levels. Finally, in obese TNF-alpha-deficient mice, circulating leptin levels were significantly lower, whereas adipose tissue leptin was higher compared with obese wild-type animals. These data provide evidence that TNF-alpha can act directly on adipocytes to regulate the release of a preformed pool of leptin, Furthermore, they suggest that the elevated adipose tissue expression of TNF-alpha that occurs in obesity may contribute to obesity-related hyperleptinemia.