Pigment Epithelium-Derived Factor Contributes to Insulin Resistance in Obesity
Pigment Epithelium-Derived Factor Contributes to Insulin Resistance in Obesity
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DOI：
10.1016/j.cmet.2009.06.001
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发表时间：
2009-07-08
期刊：
影响因子：
29
通讯作者：
Watt, Matthew J.
中科院分区：
文献类型：
--
作者：
Crowe, Seamus;Wu, Lindsay E.;Watt, Matthew J.
肥胖是胰岛素抵抗的主要危险因素;然而，与这些疾病相关的因素尚未明确。在此，我们表明，非抑制性丝氨酸蛋白酶抑制剂，色素上皮衍生因子（PEDF），在胰岛素抵抗中起着因果作用。脂肪细胞PEDF表达和血清水平在几种肥胖啮齿动物模型中升高，并在体重减轻和胰岛素致敏后降低。注射重组PEDF的瘦小鼠在高胰岛素-正常血糖钳夹期间表现出降低的胰岛素敏感性。急性PEDF给药激活了肌肉和肝脏中的促炎性丝氨酸/苏氨酸激酶c-Jun末端激酶和细胞外调节激酶，这与胰岛素信号转导减少相对应。延长PEDF给药刺激脂肪组织脂解，导致异位脂质沉积，并降低胰岛素敏感性，而在肥胖小鼠中中和PEDF增强胰岛素敏感性。总之，这些结果确定了PEDF在肥胖诱导的胰岛素抵抗中的因果作用。
Obesity is a major risk factor for insulin resistance; however, the factors linking these disorders are not well defined. Herein, we show that the noninhibitory serine protease inhibitor, pigment epithelium-derived factor (PEDF), plays a causal role in insulin resistance. Adipocyte PEDF expression and serum levels are elevated in several rodent models of obesity and reduced upon weight loss and insulin sensitization. Lean mice injected with recombinant PEDF exhibited reduced insulin sensitivity during hyperinsulinemic-euglycemic clamps. Acute PEDF administration activated the proinflammatory serine/threonine kinases c-Jun terminal kinase and extracellular regulated kinase in both muscle and liver, which corresponded with reduced insulin signal transduction. Prolonged PEDF administration stimulated adipose tissue lipolysis, resulted in ectopic lipid deposition, and reduced insulin sensitivity, while neutralizing PEDF in obese mice enhanced insulin sensitivity. Overall, these results identify a causal role for PEDF in obesity-induced insulin resistance.