瘦素对骨重建的神经调节

骨重建是骨骼保持自我更新的过程,以往认为骨重建的调节仅涉及骨骼局部的自分泌、旁分泌等方式。近年来的研究发现,中枢神经系统对骨重建的维持发挥关键作用,瘦素是其中重要的调控因子。本文简要综述瘦素通过交感神经系统、神经肽(可卡因安非他明调节转录肽,CART),以及神经介素U对骨重建的调节作用及其分子基础。     

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。     

昆虫神经肽F的研究进展

神经肽Y(Neuropeptide Y,NPY)家族作为一种神经递质,参与到脊椎动物许多生理功能的调控。神经肽F(Neuropeptide F,NPF)作为NPY在非脊椎动物中的同源肽,也具有类似的功能,目前NPF已经在许多的昆虫中得到鉴定,它一般由28~45个残基组成,C端为保守的RPRFamide结构。通过与配对的G蛋白偶联受体NPFR(Neuropeptide F receptor)结合,在昆虫的取食、酒精敏感性、攻击行为、繁殖、时钟节律和学习能力等诸多行为中发挥调节作用,但NPF/NPFR信号通路目前尚不明确。本文概述了NPF及其受体在一些模式动物上的分布及生理功能。     

昆虫神经肽F的研究进展

神经肽Y(Neuropeptide Y,NPY)家族作为一种神经递质,参与到脊椎动物许多生理功能的调控。神经肽F(Neuropeptide F,NPF)作为NPY在非脊椎动物中的同源肽,也具有类似的功能,目前NPF已经在许多的昆虫中得到鉴定,它一般由28~45个残基组成,C端为保守的RPRFamide结构。通过与配对的G蛋白偶联受体NPFR(Neuropeptide F receptor)结合,在昆虫的取食、酒精敏感性、攻击行为、繁殖、时钟节律和学习能力等诸多行为中发挥调节作用,但NPF/NPFR信号通路目前尚不明确。本文概述了NPF及其受体在一些模式动物上的分布及生理功能。     

雌激素影响物质和能量代谢的中枢机制

雌激素与糖尿病的发生和发展有密切关系。新近研究表明,雌激素受体(estrogen receptor,ER)对物质代谢和能量平衡具有重要调节作用。雌激素可由核内ER介导,通过基因组机制,或膜上ER通过磷脂酰肌醇3-激酶/蛋白激酶B及胞外信号调节激酶信号转导通路,调节下丘脑神经元摄食和厌食神经肽的表达。下丘脑ERα基因沉默小鼠表现出典型的代谢综合征症状,提示中枢ERα能够影响外周能量代谢。进一步研究发现,中枢ERα和胰岛素以及瘦素信号转导通路存在交互作用。因此,阐明中枢ER调控能量代谢的机制,可为临床防治雌激素紊乱导致的糖和能量代谢异常提供新的思路。     

瘦素信号与瘦素抵抗机制研究进展

瘦素(leptin)调控机体能量平衡(energy balance)和代谢稳态(metabolic homeostasis)。瘦素功能异常与肥胖和糖尿病等代谢性疾病密切相关。瘦素激活中枢代谢调控神经元,启动瘦素信号转导(leptin signalings),以发挥生理功能。瘦素抵抗(leptin resistance),表现为血浆瘦素水平升高,但作用减弱或消失。目前认为,下丘脑代谢调控神经元的瘦素信号转导异常是瘦素抵抗的主要机制之一。本文综述近五年来瘦素信号转导与瘦素抵抗机制研究进展。     

瘦素在哺乳动物体重调节、繁殖和免疫中的作用

瘦素(Leptin) 主要是由白色脂肪细胞分泌的、肥胖基因编码的、分子量为16 KD 的蛋白类激素。其N 端具有信号肽序列, 引导蛋白质进入分泌途径, 信号肽被切除后成为有生物学功能的成熟蛋白质。瘦素在动物的体重调节、发育与生殖、免疫和糖代谢等方面有重要作用。瘦素已经不仅仅是脂肪细胞分泌的蛋白类激素, 而是一个在许多方面发挥作用的神经内分泌调节因子。本文综述了瘦素在哺乳动物体重调节、繁殖和免疫中的作用及其调控机制, 主要包括: 动物血清瘦素浓度的季节性变化; 光周期、温度和食物等环境因子对瘦素浓度的影响; 瘦素与解偶联蛋白(Uncoupling proteins , UCPs) 在能量代谢和产热中的互作; 瘦素与下丘脑神经肽Y (Hypothalamus neuropeptide Y, NPY) 在体重调节和产热作用中的拮抗; 瘦素与甲状腺激素和胰岛素在能量代谢中的互作以及瘦素在生殖和免疫中的作用。     

神经肽CGRP、SP、NPY对软骨细胞的影响研究

近年来,由于创伤和感染等多类原因导致的骨折和骨不连等症状均是威胁到人类生命安全及生活质量的一个医学难题,为了更好地提升对于此类患者的治疗效果,有必要明确骨形成和重建等病理生理学情况以及相应的生物学机制。同时,骨组织是一类随细胞外基质的矿化,并根据其自身需求进行修复的动态组织,也是有着血管和神经支配的活性组织,所以,骨折的修复过程当中不仅含机体各类组织和细胞因子间的复杂作用,还和血液供应及神经支配紧密相连。目前,临床关于神经肽的研究逐渐增多,且越来越多的报道表明神经肽类物质能够在骨折愈合及重建过程中发挥出重要作用,原因可能和机体神经发挥相应的调控作用,并刺激骨细胞发生变化等因素有关。本文即据此展开关于神经肽CGRP(降钙素基因相关肽,Calcitonin gene-related peptide)、SP(P物质,Substance P)、NPY(神经肽Y,Neuropeptide Y)对软骨细胞影响情况的综述分析,从而更好地服务临床。     

Neural regulation of bone remodeling: Identifying novel neural molecules and pathways between brain and bone

The metabolism and homeostasis of the skeletal system have historically been considered to be associated with the endocrine system. However, this view has been expanded with the recognition of several neural pathways playing important roles in the regulation of bone metabolism via central relays. In particular, bone metabolism and homeostasis have been reported to be precisely modulated by the central neural signaling. Initiated by the finding of leptin, the axis of neural regulation on bone expands rapidly. The semaphorin–plexin system plays an important role in the cross-talk between osteoclasts and osteoblasts; a complex system has also been identified and includes neuropeptide Y and cannabinoids. These findings facilitate our understanding of the central neuropeptides and neural factors in the modulation of bone metabolism and homeostasis, and these neuronal pathways also represent an area of research scenario that identifies the novel regulation between brain and bone. These regulatory mechanisms correlate with other homeostatic networks and demonstrate a more intricate and synergetic bone biology than previously envisioned. As such, this review summarizes the current knowledge of the neural regulation of bone metabolism and homeostasis, as well as its role in skeletal diseases and discusses the emerging challenges presented in this field.     

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.     

AMP-activated protein kinase: balancing the scales

AMP-activated protein kinase (AMPK) is the central component of a protein kinase cascade that plays a key role in the regulation of energy control. AMPK is activated in response to an increase in the ratio of AMP:ATP within the cell. Activation requires phosphorylation of threonine 172 within the catalytic subunit of AMPK by an upstream kinase. The identity of the upstream kinase in the cascade remained frustratingly elusive for many years, but was recently identified as LKB1, a kinase that is inactivated in a rare hereditary form of cancer called Peutz-Jeghers syndrome. Once activated, AMPK initiates a series of responses that are aimed at restoring the energy balance within the cell. ATP-consuming, anabolic pathways, such as fatty acid synthesis and protein synthesis are switched-off, whereas ATP-generating, catabolic pathways, such as fatty acid oxidation and glycolysis, are switched-on. More recent studies have indicated, that AMPK plays an important role in the regulation of whole body energy metabolism. The adipocyte-derived hormones, leptin and adiponectin, activate AMPK in peripheral tissues, including skeletal muscle and liver, increasing energy expenditure. In the hypothalamus, AMPK is inhibited by leptin and insulin, hormones which suppress feeding, whilst ghrelin, a hormone that increases food intake, activates AMPK. Furthermore, direct pharmacological activation of AMPK in the hypothalamus by 5-aminoimidazole-4-carboxamide ribose increases food intake in rats, demonstrating that AMPK plays a direct role in the regulation of feeding. Taken together these findings indicate that AMPK has a pivotal role in regulating pathways that control both energy expenditure and energy intake.     

瘦素与软骨代谢

瘦素最初发现是在白色脂肪组织产生并且与脂肪组织量有强相关性的激素物质。它最初发现于1994年,并且在中枢神经系统起到限制食物摄入,刺激能量消耗的作用。目前发现在几乎所有的组织内都有瘦素受体的表达,而且在细胞层面瘦素参与各种各样的生物学功能,包括免疫反应、炎性疾病以及心血管、呼吸系统的病理生理过程。目前大量研究表明,瘦素在软骨代谢也发挥了重要作用,现综述如下。     

Leptin stimulates gonadotropin releasing hormone release from cultured intact hemihypothalami and enzymatically dispersed neurons

Leptin is a peptide released by adipocytes that has profound effects on central regulation of body metabolism. The present study represents an investigation into leptin effects on hypothalamic control of reproductive function, specifically on GnRH release. Adult male rats (gonadectomized or sham-operated) were used as donors of hypothalamic tissue that was used as intact hemihypothalami or as enzymatically dispersed hemihypothalami in a perifusion culture system. Continuous samples were collected at 10-min intervals for 8 to 10 hr and were assayed to measure temporal changes in GnRH release in response to various doses of leptin infused into the perifusion chambers. Leptin at the highest dose (10(-8) M) resulted in consistent and significant stimulation of GnRH release. There were no effects of treatment for surgical preparation (gonadectomy versus sham) or tissue preparation (intact versus dispersed hemihypothalami). The results of this study support the hypothesis that leptin plays a direct stimulatory role in the regulation of GnRH release. This study describes an important step in our understanding of the mechanism that connects changes in basal metabolism with reproductive function. These results indicate an intact interneuronal network is unnecessary for these leptin effects, but does not exclude a role for interneuronal networks in this regulatory pathway.     

Leptin plays a catabolic role on articular cartilage

Leptin has been shown to play a crucial role in the regulation of body weight. There is also evidence that this adipokine plays a key role in the process of osteoarthritis. However, the precise role of leptin on articular cartilage metabolism is not clear. We investigate the role of leptin on articular cartilage in vivo in this study. Recombinant rat leptin (100 μg) was injected into the knee joints of rats, 48 h later, messenger RNA (mRNA) expression and protein levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), cathepsin D, and collagen II from articular cartilage were analyzed by real-time quantitative polymerase chain reaction (PCR) and western blot. Two important aggrecanases ADAMTS-4 and -5 (a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5) were also analyzed by real-time quantitative PCR. Besides, articular cartilage was also assessed for proteoglycan/GAG content by Safranin O staining. Leptin significantly increased both gene and protein levels of MMP-2, MMP-9, cathepsin D, and collagen II, while decreased bFGF markedly in cartilage. Moreover, the gene expression of ADAMTS-4 and -5 were markedly increased, and histologically assessed depletion of proteoglycan in articular cartilage was observed after treatment with leptin. These results strongly suggest that leptin plays a catabolic role on cartilage metabolism and may be a disadvantage factor involve in the pathological process of OA.     

Leptin beyond body weight regulation--current concepts concerning its role in immune function and inflammation

Leptin, a 16 kDa non-glycosylated polypeptide produced primarily by adipocytes and released into the systemic circulation, exerts a multitude of regulatory functions including energy utilization and storage, regulation of various endocrine axes, bone metabolism, and thermoregulation. In addition to leptin's best known role as regulator of energy homeostasis, several studies indicate that leptin plays a pivotal role in immune and inflammatory response. Because of its dual nature as a hormone and cytokine, leptin can be nowadays considered the link between neuroendocrine and immune system. The increase in leptin production that occurs during infections and inflammatory processes strongly suggests that this adipokine is a part of the cytokines network which governs inflammatory/immune response and host defence mechanisms. Indeed, leptin plays a relevant role in inflammatory processes involving either innate or adaptive immune responses. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as encephalomyelitis, type I diabetes, bowel inflammation and also articular degenerative diseases such as rheumatoid arthritis and osteoarthritis. Although the mechanisms by which leptin exerts its action as modulator of inflammatory/immune response are likely to be more complex than predicted and far to be completely depicted, there is a general consensus about its pivotal role as pro-inflammatory and immune-modulating agent. Here, we review the most recent advances on leptin biology with a particular attention to its adipokine facet, even though its role as metabolic hormone will be also addressed.     

Understanding leptin-dependent regulation of skeletal homeostasis

Despite growing evidence for adipose tissue regulation of bone mass, the role of the adipokine leptin in bone remodeling remains controversial. The majority of in vitro studies suggest leptin enhances osteoblastic proliferation and differentiation while inhibiting adipogenic differentiation from marrow stromal cells. Alternatively, some evidence demonstrates either no effect or a pro-apoptotic action of leptin on stromal cells. Similarly, in vivo work has demonstrated both positive and negative effects of leptin on bone mass. Most of the literature supports the idea that leptin suppresses bone mass by acting in the brainstem to reduce serotonin-dependent sympathetic signaling from the ventromedial hypothalamus to bone. However, other studies have found partly or entirely contrasting actions of leptin. Recently one study found a significant effect of surgery alone with intracerebroventricular administration of leptin, a technique crucial for understanding centrally-mediated leptin regulation of bone. Thus, two mainstream hypotheses for the role of leptin on bone emerge: 1) direct regulation through increased osteoblast proliferation and differentiation and 2) indirect suppression of bone formation through a hypothalamic relay. At the present time, it remains unclear whether these effects are relevant in only extreme circumstances (i.e. models with complete deficiency) or play an important homeostatic role in the regulation of peak bone acquisition and skeletal remodeling. Ultimately, determining the actions of leptin on the skeleton will be critical for understanding how the obesity epidemic may be impacting the prevalence of osteoporosis.     

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。     

Action of leptin on bone and its relationship to menopause

Backround: Leptin a cytokine protein secreted by adipose tissue raises considerable interest as a potential mediator of the protective effects of fat mass on bone tissue. After menopause heavier women conserve bone mass better than those with lower body weight. The protective effect of obesity on bone mass has been ascribed to a high body fat content. As Leptin levels reflect the body fat content it has emerged as a possible mediator of these protective effects. Methods: A search of the available literature focused on the role of leptin on bone tissue. Results: Both peripheral and central action of leptin on bone metabolism have been proposed. In vitro and in vivo evidence supports the hypothesis that leptin can act directly or indirectly on bone remodelling by modulating both osteoblast and osteoclast activities. However, studies in humans have not yet been able to confirm these actions possibly because of the shifting balance between stimulatory direct action and suppressive indirect action of leptin on bones via the hypothalamus. The effects of oestrogen decline and deficiency during natural or artificially induced menopause and administration of hormone replacement therapy has on leptin production remains controversial. Various studies have shown differences in leptin values in pre- and postmenopausal women. The existing clinical data on this issue are discordant. Conclusion: Larger clinical studies are necessary to clarify leptin's role in vivo and to assess the contribution of the central and peripheral role of leptin in the overall maintenance of bone turnover in human beings.