Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance
Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance
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DOI：
10.2337/db15-0941
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发表时间：
2015-09
期刊：
影响因子：
7.7
通讯作者：
S. Wueest;Flurin Item;Fabrizio C. Lucchini;T. D. Challa;Werner Müller-;M. Blüher;D. Konrad
中科院分区：
文献类型：
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作者：
S. Wueest;Flurin Item;Fabrizio C. Lucchini;T. D. Challa;Werner Müller-;M. Blüher;D. Konrad
肝脏脂肪变性和胰岛素抵抗是最常见的代谢紊乱之一，与肥胖和2型糖尿病密切相关。然而，肥胖与肝脏脂质积聚和胰岛素抵抗的潜在机制尚不完全清楚。糖蛋白130（gp 130）是所有白细胞介素6（IL-6）细胞因子的共同信号转导子。我们提供了gp 130介导的脂肪组织脂解促进肝脂肪变性和胰岛素抵抗的证据。在肥胖小鼠中，脂肪细胞特异性gp 130缺失减少了基础脂解，增强了胰岛素抑制肠系膜脂肪细胞脂解的能力，但对附睾脂肪细胞没有影响。与此同时，肥胖基因敲除小鼠门静脉游离脂肪酸水平降低，但体循环中的游离脂肪酸水平没有降低。值得注意的是，脂肪细胞特异性gp 130基因敲除的小鼠受到保护，免受高脂饮食诱导的肝脂肪变性以及胰岛素抵抗。在人类中，网膜而非皮下IL-6 mRNA表达与肝脏脂质蓄积呈正相关（r = 0.31，P < 0.05），与高胰岛素-正葡萄糖钳夹葡萄糖输注率呈负相关（r =-0.28，P < 0.05）。结果表明，IL-6精氨酸诱导的脂解作用可能仅限于肠系膜白色脂肪组织，并导致肝脏胰岛素抵抗和脂肪变性。因此，阻断（肠系膜）脂肪细胞中的IL-6细胞因子信号传导可能是一种新的方法来钝化肥胖症中有害的脂肪-肝脏串扰。
Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin’s ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet–induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = −0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.