PKA参与瘦素敏感度调控

<正>瘦素(leptin)主要由白色脂肪细胞(white adipocytes)分泌,其受体位于下丘脑、皮层、海马、中脑等脑区;因而,瘦素以中枢调节的形式,对机体能量平衡与代谢稳态等功能发挥重要调控作用。目前,瘦素敏感度降低引发的"瘦素抵抗"(leptin resistance)被认为是肥胖与二型糖尿病的重要病因。最新的一项研究揭示,蛋白激酶A(cA MP-dependent protein kinase-A,PKA),在下丘脑代谢调控神经元,参与调节瘦素敏感度。     

胰岛素和瘦素抵抗的重要调控因子:细胞因子信号转导抑制因子-3

细胞因子信号转导抑制因子-3(Suppressor of Cytokine Signaling-3,SOCS-3)是细胞信号转导生理抑制剂家族重要成员之一,主要参与负调控生长激素、白介素(IL),肿瘤坏死因子(TNF)等细胞因子信号转导.最近发现,SOCS-3在胰岛素和瘦素抵抗中具有重要调控功能,且与糖尿病关系密切,是未来糖尿病基因治疗的新靶点.该文综述了近年来SOCS-3结构及其对胰岛素和瘦素抵抗的调控机制研究进展,并探讨SOCS-3在糖尿病中的作用.     

瘦素在禽类中的研究进展

瘦素(leptin)是一种主要作用于下丘脑的重要激素,起到调控摄食和能量消耗的作用。另外,国内外越来越多的研究表明,leptin与动物的代谢、发育、繁殖和免疫调节等均有密切的联系。但是上述研究大多在哺乳动物中进行,在禽类中的研究还在起步阶段。现有的研究表明,禽类的leptin及leptin受体的作用与哺乳动物相比都有其特殊性。本文首先分析了禽类leptin及leptin受体的特点,在此基础上,从摄食、生长发育和繁殖三个方面综述了leptin对禽类的作用及可能机制。     

瘦素在糖脂代谢中的调控作用

瘦素（leptin）是OB基因的编码产物,由脂肪细胞分泌,具有广泛的生理学功能.瘦素可通过作用于中枢神经系统与外周组织等途径在糖脂代谢调控、能量代谢、生殖发育及免疫调节过程中起重要作用.不同剂量、不同作用时间,也可导致瘦素产生不同的生理学作用.近年来,随着肥胖及糖尿病在全球范围内成为流行病,瘦素在糖脂代谢中的调控作用引起了人们的广泛关注.现有的研究已发现,瘦素抵抗与胰岛素抵抗之间具有重要的关联性,揭示瘦素功能异常在肥胖诱发的糖脂代谢紊乱过程中起着重要的作用.本文将对瘦素在机体糖脂代谢中的调控作用进行综述和讨论.     

运动改善肥胖症瘦素抵抗及其机制研究进展

大部分肥胖患者体内出现瘦素抵抗,表现为血清瘦素水平异常升高,但机体对瘦素不敏感或无反应,使瘦素抑制食欲、增加能量消耗和降低血糖等功能不能有效发挥.减轻瘦素抵抗被认为是治疗肥胖及肥胖相关疾病的有效途径.运动减轻肥胖、改善糖脂代谢和增强胰岛素敏感性的作用与运动降低瘦素水平、改善瘦素抵抗密切相关.本文在概述瘦素实现生理功能的机制、肥胖症的中枢及外周瘦素抵抗的基础上,主要综述近年来运动减轻肥胖症瘦素抵抗机制的研究进展,包括减轻高瘦素血症、改善中枢和外周瘦素抵抗,以期为运动防治肥胖机制的研究提供新视角.     

非酒精性脂肪性肝病大鼠肝组织瘦素受体表达的变化

目的检测高脂饮食诱发的非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)大鼠肝组织瘦素受体的表达,探讨NAFLD瘦素抵抗的发生机制及瘦素抵抗在NAFLD发病中的作用.方法采用高脂饮食制备Wistar大鼠NAFLD模型;ELISA法测定大鼠血清瘦素(leptin,LP)浓度;全自动生化分析仪测血清甘油三酯(triglyceride,TG)、空腹血糖(fasting blood glucose,FBG),比色法测游离脂肪酸(free fatty acid,FFA),放射免疫法测空腹血清胰岛素(fasting insulin,FINS),计算空腹状态下胰岛素抵抗指数;对肝组织分别进行HE染色、苏丹Ⅳ染色、瘦素受体免疫组化染色,并进行半定量分析.利用SAS 8.0统计软件处理实验数据.结果模型组大鼠肝组织瘦素受体表达比正常组明显减弱,且与血清瘦素浓度、游离脂肪酸、胰岛素敏感指数、肝细胞脂变、炎症活动度显著负相关,相关系数分别为r = -0.83,-0.71, -0.65,-0.83, -0.87.多元线性回归分析显示,瘦素受体表达减弱是肝脂变的独立影响因素.结论肝组织瘦素受体表达减弱是NAFLD瘦素抵抗的重要病理机制之一,瘦素抵抗与胰岛素抵抗相互作用,共同促进了脂肪肝的发生发展.     

瘦素水平与代谢综合症的关系

随着代谢综合症在世界范围内的广为流行,已经引起人们的高度重视.代谢综合征以肥胖和代谢异常为特征,胰岛素抵抗为主要的病理机制.瘦素主要来源于脂肪组织,是调节体内脂肪储量和维持能量平衡的一种内分泌激素.瘦素缺乏和瘦素抵抗不仅可以直接引起胰岛素抵抗,而且可以通过导致肥胖继而参与胰岛素抵抗的发生,最终引起代谢综合征.瘦素作为一种新的代谢综合征致病因子,参与代谢综合征的发生发展,故调节瘦素水平为临床治疗代谢综合症提供了新的思路和方法.本文综述了瘦素水平与代谢综合症的关系,以及调节瘦素水平治疗代谢综合征的方法.     

长沙市肥胖小学生血清瘦素水平的变化及其影响因素分析

目的:探讨长沙市肥胖小学生血清瘦素(leptin)水平的变化及其影响因素.方法:长沙市5所小学7～12周岁学龄儿童中随机抽取单纯性肥胖儿童119名和正常体重儿童103名,分别测定腰围(WC),臀围,腰臀比(WHR),双能X线骨密度仪(DEXA)测量体脂百分比(%BF),并检测血清甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、空腹血糖(FBG)和空腹胰岛素(FINS),计算稳态模型胰岛素抵抗指数(HOMA-IR),ELISA法测血清瘦素(Leptin).结果:肥胖小学生血清瘦素水平显著高于正常儿童(P<0.01),肥胖小学生瘦素水平与BMI、WC、WHR、%BF、TG、LDL-C呈明显正相关,与HDL-C呈明显负相关,多元逐步回归分析表明FINS、HOMA-IR、BMI、TG、LDL-C及%BF是肥胖儿童血清瘦素水平的主要相关因素.结论:长沙市肥胖小学生血清瘦素水平升高且与体脂、胰岛素抵抗和血脂明显相关.     

运动后瘦素水平的变化及其对骨代谢的影响

瘦素(leptin)的生理作用很多,其对骨代谢的影响可以通过中枢和外周两个机制来实现.运动可以影响人体骨代谢,但运动后血清瘦素水平的变化不一,可能是因为瘦素可以通过多种下丘脑-垂体轴途径影响骨代谢,如下丘脑-垂体-肾上腺轴、下丘脑-垂体-甲状腺轴、下丘脑-垂体-生长激素轴等等,各途径作用结果不一致,致使不同的运动形式对瘦素的影响不同.本文对运动后瘦素水平改变及其对骨代谢的作用予以综述.     

Leptin

Leptin is an adipocyte hormone that signals nutritional status to the central nervous system (CNS) and peripheral organs. Leptin is also synthetized in the placenta and in gastrointestinal tract, although its role in these tissues is not yet clear. Circulating concentrations of leptin exhibit pulsatility and circadian rhythmicity. The levels of plasma leptin vary directly with body mass index and percentage body fat, and leptin contributes to the regulation of body weight. Leptin plasma concentrations are also influenced by metabolic hormones, sex, and body energy requirements. Defects in the leptin signaling pathway result in obesity in animal models. Only a few obese humans have been identified with mutations in the leptin gene or in the leptin receptor; however, most cases of obesity in humans are associated with high leptin levels. Thus, in humans obesity may represent a state of leptin resistance. Minute-to-minute fluctuations in peripheral leptin concentrations influence the activity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes, indicating that leptin may be a modulator of reproduction, stress-related endocrine function, and behavior. This suggests potential roles for leptin or its antagonists in the diagnosis, pathophysiology and treatment of several human diseases.     

Leptin

It is well established that the adipocyte-derived hormone leptin is an important circulating satiety factor that regulates body weight and food intake via its actions on specific hypothalamic nuclei. However, there is growing evidence that leptin and its receptors are widely expressed throughout the brain, in regions not generally associated with energy homeostasis, such as cortex, cerebellum, brainstem, basal ganglia, and hippocampus. In this review the author discusses recent advances made in leptin neurobiology, with particular emphasis on the role of this endocrine peptide in normal and pathophysiological hippocampal function.     

Leptin signalling

The identification of leptin as the product of the obesity (ob) gene has been followed by extensive research identifying a wide spectrum of physiological effects elicited by this adipose-derived hormone. These effects are mediated via a family of cytokine-like receptor isoforms distributed in both the central nervous system and periphery. The signal transduction pathways regulated by leptin are diverse and include those characteristic of both cytokine and growth factor receptor signalling. This review describes the structure and function of leptin receptors and summarizes recent progress that has been made in characterizing the increasing number of signal transduction pathways regulated by leptin.     

Leptin and exercise

Short-term exercise (<60 min) studies suggest that leptin concentrations are not acutely affected in healthy males and females. Most reports of reductions in serum leptin may be attributed to circadian rhythms or hemoconcentration. For long-term (> or =60 min) exercise, a reduction in leptin concentrations reported from 1 to 3 hr of running or cycling has been attributed to diurnal reduction in circulating leptin, independent of exercise. Exercise that produces a sufficient energy imbalance (kilocalorie intake versus kilocalorie expenditure) suppresses 24-hr mean and amplitude of the diurnal rhythm of leptin in women. Suppression of leptin concentrations may be counterbalanced by feeding and may explain consistent reports of reductions in leptin concentrations following extreme bouts of exercise such as marathons or ultramarathons. In addition, leptin concentrations are reduced 48 hr after long-term aerobic exercise and long-term resistance exercise is associated with delayed leptin reduction 9 hr postexercise. Training studies have documented that short-term exercise training (< or =12 weeks) does not affect leptin levels, with the exception of patients with type 2 diabetes. Exercise training protocols that result in reduced fat mass will lower leptin concentrations, thus, most investigators have reported leptin concentrations after accounting for fat loss. There are disparate findings concerning long-term (>12 weeks) training studies, with a number of studies finding no effect of training on leptin concentrations other than effects induced by fat loss, and other studies finding reductions in leptin concentrations after accounting for fat loss. Exercise training-induced reductions in leptin levels have been attributed to alterations in energy balance, improvements in insulin sensitivity, alterations in lipid metabolism, and unknown factors. Hormone replacement does not seem to affect leptin adaptations to training. Patients with type 2 diabetes show delayed effects of short-term resistance exercise on leptin concentrations, reduced leptin levels with long-term training, and appear to be more sensitive to training-induced leptin adaptations than other populations.     

Leptin in pregnancy

Leptin is a polypeptide hormone that aids in the regulation of body weight and energy homeostasis and is linked to a variety of reproductive processes in both animals and humans. Thus, leptin may help regulate ovarian development and steroidogenesis and serve as either a primary signal initiating puberty or as a permissive regulator of sexual maturation. Perhaps significantly, peripheral leptin concentrations, adjusted for adiposity, are dramatically higher in females than in males throughout life. During primate pregnancy, maternal levels that arise from adipose stores and perhaps the placenta increase with advancing gestational age. Proposed physiological roles for leptin in pregnancy include the regulation of conceptus growth and development, fetal/placental angiogenesis, embryonic hematopoiesis, and hormone biosynthesis within the maternal-fetoplacental unit. The specific localization of both leptin and its receptor in the syncytiotrophoblast implies autocrine and/or paracrine relationships in this endocrinologically active tissue. Interactions of leptin with mechanisms regulating pre-eclampsia and maternal diabetes have also been suggested. Collectively, therefore, reports suggest that a better understanding of the regulation of leptin and its role(s) throughout gestation may eventually impact those causes of human perinatal morbidity and mortality that are exacerbated by intrauterine growth retardation, macrosomia, placental insufficiency, or prematurity.     

Leptin in immunology

Leptin is an adipokine which conveys information on energy availability. In humans, leptin influences energy homeostasis and regulates neuroendocrine function primarily in states of energy deficiency. As a cytokine, leptin also affects thymic homeostasis and, similar to other proinflammatory cytokines, leptin promotes Th1 cell differentiation and cytokine production. We review herein recent advances on the role of leptin in the pathophysiology of immune responses.     

Leptin and cancer

The prevalence of obesity has markedly increased over the past two decades, especially in the industrialized countries. While the impact of excess body weight on the development of cardiac disease and diabetes has been well documented, the link between obesity and carcinogenesis is just being recognized. This review will focus on the link between leptin, a cytokine that is elevated in obese individuals, and cancer development. First, we briefly discuss the biological functions of leptin and its signaling pathways. Then, we summarize the effects of leptin on different cancer types in experimental cellular and animal models. Next, we analyze epidemiological data on the relationship between obesity and the presence of cancer or cancer risk in patients. Finally, leptin as a target for cancer treatment and prevention will be discussed.     

Kinetics of Leptin Binding to the Q223R Leptin Receptor

Studies in human populations and mouse models of disease have linked the common leptin receptor Q223R mutation to obesity, multiple forms of cancer, adverse drug reactions, and susceptibility to enteric and respiratory infections. Contradictory results cast doubt on the phenotypic consequences of this variant. We set out to determine whether the Q223R substitution affects leptin binding kinetics using surface plasmon resonance (SPR), a technique that allows sensitive real-time monitoring of protein-protein interactions. We measured the binding and dissociation rate constants for leptin to the extracellular domain of WT and Q223R murine leptin receptors expressed as Fc-fusion proteins and found that the mutant receptor does not significantly differ in kinetics of leptin binding from the WT leptin receptor. (WT: k_a 1.76×10⁶±0.193×10⁶ M⁻¹ s⁻¹, k_d 1.21×10⁻⁴±0.707×10⁻⁴ s⁻¹, K_D 6.47×10⁻¹¹±3.30×10⁻¹¹ M; Q223R: k_a 1.75×10⁶±0.0245×10⁶ M⁻¹ s⁻¹, k_d 1.47×10⁻⁴±0.0505×10⁻⁴ s⁻¹, K_D 8.43×10⁻¹¹±0.407×10⁻¹¹ M). Our results support earlier findings that differences in affinity and kinetics of leptin binding are unlikely to explain mechanistically the phenotypes that have been linked to this common genetic variant. Future studies will seek to elucidate the mechanism by which this mutation influences susceptibility to metabolic, infectious, and malignant pathologies.