Laboratory of Molecular and Cellular Endocrinology, Department of Internal Medicine, University of Turin, Corso Dogliotti 14-10126 Turin, Italy.
FASEB J. 2012 Aug;26(8):3393-411. doi: 10.1096/fj.11-201343. Epub 2012 May 17.
The metabolic actions of the ghrelin gene-derived peptide obestatin are still unclear. We investigated obestatin effects in vitro, on adipocyte function, and in vivo, on insulin resistance and inflammation in mice fed a high-fat diet (HFD). Obestatin effects on apoptosis, differentiation, lipolysis, and glucose uptake were determined in vitro in mouse 3T3-L1 and in human subcutaneous (hSC) and omental (hOM) adipocytes. In vivo, the influence of obestatin on glucose metabolism was assessed in mice fed an HFD for 8 wk. 3T3-L1, hSC, and hOM preadipocytes and adipocytes secreted obestatin and showed specific binding for the hormone. Obestatin prevented apoptosis in 3T3-L1 preadipocytes by increasing phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 signaling. In both mice and human adipocytes, obestatin inhibited isoproterenol-induced lipolysis, promoted AMP-activated protein kinase phosphorylation, induced adiponectin, and reduced leptin secretion. Obestatin also enhanced glucose uptake in either the absence or presence of insulin, promoted GLUT4 translocation, and increased Akt phosphorylation and sirtuin 1 (SIRT1) protein expression. Inhibition of SIRT1 by small interfering RNA reduced obestatin-induced glucose uptake. In HFD-fed mice, obestatin reduced insulin resistance, increased insulin secretion from pancreatic islets, and reduced adipocyte apoptosis and inflammation in metabolic tissues. These results provide evidence of a novel role for obestatin in adipocyte function and glucose metabolism and suggest potential therapeutic perspectives in insulin resistance and metabolic dysfunctions.
胃饥饿素基因衍生肽肥胖抑制素的代谢作用尚不清楚。我们研究了肥胖抑制素在体外对脂肪细胞功能的作用，以及在高脂肪饮食（HFD）喂养的小鼠体内对胰岛素抵抗和炎症的作用。在体外，在小鼠 3T3-L1 脂肪细胞和人皮下（hSC）和网膜（hOM）脂肪细胞中，确定了肥胖抑制素对细胞凋亡、分化、脂肪分解和葡萄糖摄取的影响。在体内，评估了肥胖抑制素对 HFD 喂养 8 周的小鼠葡萄糖代谢的影响。3T3-L1、hSC 和 hOM 前体脂肪细胞和脂肪细胞分泌肥胖抑制素，并显示出对激素的特异性结合。肥胖抑制素通过增加磷酸肌醇 3-激酶（PI3K）/Akt 和细胞外信号调节激酶（ERK）1/2 信号通路来防止 3T3-L1 前体脂肪细胞凋亡。在小鼠和人脂肪细胞中，肥胖抑制素抑制异丙肾上腺素诱导的脂肪分解，促进 AMP 激活的蛋白激酶磷酸化，诱导脂联素分泌，并减少瘦素分泌。肥胖抑制素还增强了无论是否存在胰岛素的葡萄糖摄取，促进 GLUT4 易位，并增加 Akt 磷酸化和 SIRT1（SIRT1）蛋白表达。通过小干扰 RNA 抑制 SIRT1 减少了肥胖抑制素诱导的葡萄糖摄取。在 HFD 喂养的小鼠中，肥胖抑制素降低了胰岛素抵抗，增加了胰岛的胰岛素分泌，并减少了代谢组织中脂肪细胞的凋亡和炎症。这些结果为肥胖抑制素在脂肪细胞功能和葡萄糖代谢中的新作用提供了证据，并提示了在胰岛素抵抗和代谢功能障碍中的潜在治疗前景。
