The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway
The Acute-Phase Protein Orosomucoid Regulates Food Intake and Energy Homeostasis via Leptin Receptor Signaling Pathway
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急性期蛋白 Orosumucoid 通过瘦素受体信号通路调节食物摄入和能量稳态
DOI：
10.2337/db15-1193
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发表时间：
2016-06-01
期刊：
影响因子：
7.7
通讯作者：
Liu, Xia
中科院分区：
文献类型：
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作者：
Sun, Yang;Yang, Yili;Liu, Xia
急性时相蛋白orosomucid(ORM)在体内外表现出多种活性，尤其是调节免疫和药物转运。我们在这项研究中发现，缺乏ORM1的小鼠表现出异常的能量平衡，其特征是体重和脂肪质量增加。进一步的研究发现，在高脂饮食(HFD)诱导肥胖的小鼠和由于瘦素受体(Lepr)突变而自发肥胖的db/db小鼠的血清、肝脏和脂肪组织中，ORM(主要是ORM1)显著增加。静脉或腹腔注射外源性ORM可减少C57BL/6、HFD和瘦素缺陷ob/ob小鼠的摄食量，这在db/db小鼠中是不存在的，在弓状核(ARC)Lepr基因敲除的小鼠中显著减少，而在ARC中强制表达ORM1则显著降低摄食量、体重和血清胰岛素水平。此外，我们还发现ORM能够直接与Lepr结合，并在下丘脑组织和来源于下丘脑肿瘤的GT1-7细胞中激活受体介导的JAK2-STAT3信号。这些数据表明，ORM可能通过Lepr来调节食物摄入量和能量平衡，以响应营养状况。调节ORM的表达是治疗肥胖和相关代谢紊乱的一种新策略。
The acute-phase protein orosomucoid (ORM) exhibits a variety of activities in vitro and in vivo, notably modulation of immunity and transportation of drugs. We found in this study that mice lacking ORM1 displayed aberrant energy homeostasis characterized by increased body weight and fat mass. Further investigation found that ORM, predominantly ORM1, is significantly elevated in sera, liver, and adipose tissues from the mice with high-fat diet (HFD)-induced obesity and db/db mice that develop obesity spontaneously due to mutation in the leptin receptor (LepR). Intravenous or intraperitoneal administration of exogenous ORM decreased food intake in C57BL/6, HFD, and leptin-deficient ob/ob mice, which was absent in db/db mice and was significantly reduced in mice with arcuate nucleus (ARC) LepR knockdown, whereas enforced expression of ORM1 in ARC significantly decreased food intake, body weight, and serum insulin level. Furthermore, we found that ORM is able to bind directly to LepR and activate the receptor-mediated JAK2-STAT3 signaling in hypothalamus tissue and GT1-7 cells, which was derived from hypothalamic tumor. These data indicated that ORM could function through LepR to regulate food intake and energy homeostasis in response to nutrition status. Modulating the expression of ORM is a novel strategy for the management of obesity and related metabolic disorders.