Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Endocrinology. 2014 Mar;155(3):941-50. doi: 10.1210/en.2013-1813. Epub 2014 Jan 1.
Pigment epithelium-derived factor (PEDF) plays an important role in insulin resistance (IR). The study aims to investigate the effect of rosiglitazone, an insulin sensitizer, on PEDF production and release both in vivo and in vitro. Male SD rats were divided into normal control group, high-fat group, and rosiglitazone group. Hyperinsulinemic euglycemic clamp was performed to evaluate insulin sensitivity. IR models of 3T3-L1 adipocytes and HepG2 cells were established by the hyperinsulinemic method. Glucose uptake was examined to validate IR of adipocytes, and phosphorylation of protein kinase B and glycogen synthesis kinase 3β were examined to validate IR of HepG2 cells. Rosiglitazone, 2-chloro-5-nitro-N-phenylbenzamide (GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ), and compound C (inhibitor of AMP-activated protein kinase [AMPK]) were used for the in vitro intervention. In vivo, the high-fat group showed increased serum PEDF levels, which negatively correlated with insulin sensitivity, whereas the rosiglitazone treatment decreased the serum PEDF and down-regulated PEDF expression in fat and liver of the obese rats, concomitant with significantly enhanced insulin sensitivity. In vitro, the IR cells showed increased PEDF secretion and expression, whereas rosiglitazone lowered PEDF secretion and expression, accompanied with increased insulin sensitivity. Interestingly, combination with 2-chloro-5-nitro-N-phenylbenzamide did not influence the effect of rosiglitazone on PEDF. However, rosiglitazone stimulated AMPK phosphorylation in fat and liver of the obese rats, whereas in vitro, when combined with compound C, the effect of rosiglitazone on PEDF was abrogated. In summary, rosiglitazone inhibits the expression and secretion of PEDF in fat and liver via promoting AMPK phosphorylation rather than peroxisome proliferator-activated receptor-γ, and changes of PEDF induced by rosiglitazone are closely associated with IR improvement.
色素上皮衍生因子（PEDF）在胰岛素抵抗（IR）中发挥重要作用。本研究旨在探讨胰岛素增敏剂罗格列酮对体内和体外 PEDF 产生和释放的影响。雄性 SD 大鼠分为正常对照组、高脂组和罗格列酮组。通过高胰岛素-正常血糖钳夹试验评估胰岛素敏感性。采用高胰岛素法建立 3T3-L1 脂肪细胞和 HepG2 细胞的 IR 模型。通过葡萄糖摄取实验验证脂肪细胞的 IR，通过磷酸化蛋白激酶 B 和糖原合成激酶 3β实验验证 HepG2 细胞的 IR。使用 2-氯-5-硝基-N-苯甲酰胺（过氧化物酶体增殖物激活受体-γ抑制剂，GW9662）和化合物 C（AMP 激活的蛋白激酶 [AMPK] 抑制剂）进行体外干预。在体内，高脂组血清 PEDF 水平升高，与胰岛素敏感性呈负相关，而罗格列酮治疗降低了肥胖大鼠脂肪和肝脏中的血清 PEDF 水平，并下调了 PEDF 的表达，同时显著提高了胰岛素敏感性。在体外，IR 细胞 PEDF 分泌和表达增加，而罗格列酮降低了 PEDF 的分泌和表达，同时增加了胰岛素敏感性。有趣的是，与 2-氯-5-硝基-N-苯甲酰胺联合使用并不影响罗格列酮对 PEDF 的作用。然而，罗格列酮在肥胖大鼠的脂肪和肝脏中刺激 AMPK 磷酸化，而在体外，当与化合物 C 联合使用时，罗格列酮对 PEDF 的作用被阻断。总之，罗格列酮通过促进 AMPK 磷酸化而非过氧化物酶体增殖物激活受体-γ抑制脂肪和肝脏中 PEDF 的表达和分泌，而罗格列酮引起的 PEDF 变化与 IR 改善密切相关。
