Campfield L A, Smith F J, Burn P
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
Horm Metab Res. 1996 Dec;28(12):619-32. doi: 10.1055/s-2007-979867.
OB protein (also known as leptin), a previously unknown protein signal, is secreted from adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks that regulate ingestive behavior and energy balance. OB protein provides a communication link from fat tissue and the brain. Rapidly accumulating evidence suggests that OB protein appears to play a major role in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energy balance in rodents, primates and humans. The field has rapidly moved from cloning of the ob gene to demonstration of complex regulation of ob gene expression in adipose tissue in rats and humans, and then the demonstration of potent biological activity of OB protein in ob/ob, diet-induced, and lean mice as well as obese and lean rats but not in db/db obese mice. A significant milestone was our demonstration that central administration of OB protein lead to reductions in food intake, body weight and alterations in metabolism consistent with activation of the autonomic nervous system. These findings were followed by the identification of a central binding site for labelled OB protein in the choroid plexus in ob/ob, db/db and lean mice as well as lean and obese Zucker rats. The expression cloning of a central receptor, OB-R, from the mouse choroid plexus soon followed. The OB-R receptor was found to be expressed in the choroid plexus, the hypothalamus as well as several peripheral tissues. OB-R exists in multiple forms; the two major forms are a short form (with a truncated intracellular domain) and long form (with the complete intracellular domain). The long form is thought to be the form that signals and mediates the biological effects of OB protein. Initial in situ hybridization studies have demonstrated the mRNA for the long form OB-R receptor to be localized to the hypothalamus as well as peripheral sites. Recently, it was demonstrated that the db gene encodes the OB-R receptor. Evidence has been provided for a specific transport system for OB protein to cross the blood-brain-barrier and enter the brain of mice, rats and humans. The rate of transport can be decreased by high plasma concentrations of OB protein. Thus, reduced entry of OB protein to the brain may be one of the mechanisms of reduced sensitivity of the OB protein pathway in obese individuals. OB protein appears to also play a role in the important neuroendocrine adaptive responses to fasting and in the control of reproduction. Therapeutic approaches to the treatment of obesity based on OB protein ranging from OB protein by injection to OB-R receptor agonists and to upregulation of OB signalling pathways are under intense investigation.
OB蛋白（也称为瘦素）是一种此前未知的蛋白质信号，由脂肪组织分泌，在血液中循环，可能与一类结合蛋白结合，并作用于调节摄食行为和能量平衡的中枢神经网络。OB蛋白提供了脂肪组织与大脑之间的通讯联系。迅速积累的证据表明，OB蛋白似乎通过协调调节啮齿动物、灵长类动物和人类的摄食行为、新陈代谢、自主神经系统和身体能量平衡，在控制身体脂肪储存方面发挥着重要作用。该领域已迅速从ob基因的克隆发展到证明大鼠和人类脂肪组织中ob基因表达的复杂调控，然后证明OB蛋白在ob/ob小鼠、饮食诱导肥胖小鼠和瘦小鼠以及肥胖和瘦大鼠中具有强大的生物活性，但在db/db肥胖小鼠中则没有。一个重要的里程碑是我们证明向中枢给予OB蛋白会导致食物摄入量减少、体重下降以及新陈代谢改变，这与自主神经系统的激活一致。这些发现之后，在ob/ob小鼠、db/db小鼠和瘦小鼠以及瘦和肥胖的 Zucker 大鼠的脉络丛中鉴定出了标记OB蛋白的中枢结合位点。随后很快从小鼠脉络丛中克隆出了中枢受体OB-R。发现OB-R受体在脉络丛、下丘脑以及几个外周组织中表达。OB-R有多种形式；两种主要形式是短形式（细胞内结构域截短）和长形式（细胞内结构域完整）。长形式被认为是发出信号并介导OB蛋白生物学效应的形式。最初的原位杂交研究表明，长形式OB-R受体的mRNA定位于下丘脑以及外周部位。最近，已证明db基因编码OB-R受体。已经有证据表明存在一种特定的转运系统，可使OB蛋白穿过血脑屏障并进入小鼠、大鼠和人类的大脑。高血浆浓度的OB蛋白可降低转运速率。因此，OB蛋白进入大脑的减少可能是肥胖个体中OB蛋白途径敏感性降低的机制之一。OB蛋白似乎在对禁食的重要神经内分泌适应性反应以及生殖控制中也发挥作用。基于OB蛋白的肥胖治疗方法，从注射OB蛋白到OB-R受体激动剂以及上调OB信号通路，都在进行深入研究。
