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Non-sympathetic control of brown adipose tissue. 褐色脂肪组织的非交感神经控制。
Pub Date : 2015-08-01 Epub Date: 2015-08-04 DOI: 10.1038/ijosup.2015.10
R Cereijo, J Villarroya, F Villarroya

The thermogenic activity of brown adipose tissue (BAT) in the organism is tightly regulated through different processes, from short-term induction of uncoupling protein-1-mediated mitochondrial proton conductance to complex processes of BAT recruitment, and appearance of the beige/brite adipocytes in white adipose tissue (WAT), the so-called browning process. The sympathetic nervous system is classically recognized as the main mediator of BAT activation. However, novel factors capable of activating BAT through non-sympathetic mechanisms have been recently identified. Among them are members of the bone morphogenetic protein family, with likely autocrine actions, and activators of nuclear hormone receptors, especially vitamin A derivatives. Multiple endocrine factors released by peripheral tissues that act on BAT have also been identified. Some are natriuretic peptides of cardiac origin, whereas others include irisin, originating in skeletal muscle, and fibroblast growth factor-21, mainly produced in the liver. These factors have cell-autonomous effects in brown adipocytes, but indirect effects in vivo that modulate sympathetic activity toward BAT cannot be excluded. Moreover, these factors can affect to different extents such as the activation of existing BAT, the induction of browning in WAT or both. The identification of non-sympathetic controllers of BAT activity is of special biomedical interest as a prerequisite for developing pharmacological tools that influence BAT activity without the side effects of sympathomimetics.

生物体内棕色脂肪组织(BAT)的产热活性受到不同过程的严格调控,从短期诱导解偶联蛋白-1介导的线粒体质子电导到复杂的BAT募集过程,以及白色脂肪组织(WAT)中米色/白白色脂肪细胞的出现,即所谓的褐变过程。交感神经系统通常被认为是BAT激活的主要介质。然而,最近发现了能够通过非交感机制激活BAT的新因子。其中包括骨形态发生蛋白家族的成员,可能具有自分泌作用,以及核激素受体的激活剂,特别是维生素A衍生物。外周组织释放的多种内分泌因子也作用于BAT。其中一些是源自心脏的利钠肽,而其他包括源自骨骼肌的鸢尾素和主要产生于肝脏的成纤维细胞生长因子-21。这些因素在棕色脂肪细胞中具有细胞自主作用,但不能排除体内调节交感神经活动的间接作用。此外,这些因素可以在不同程度上影响,如激活现有BAT,诱导WAT褐变或两者兼而有之。识别BAT活性的非交感神经控制者具有特殊的生物医学意义,是开发影响BAT活性而不产生交感神经模拟副作用的药理学工具的先决条件。
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引用次数: 22
The role of omega-3 fatty acid receptor GPR120 in insulin resistance. omega-3脂肪酸受体GPR120在胰岛素抵抗中的作用。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.5
D Y Oh, E Walenta

Obesity is the dominant cause of acquired insulin resistance, and it is the epidemic of obesity in the United States that is driving the markedly increasing incidence of type 2 diabetes. Adipocyte dysfunction and chronic low-grade adipose tissue (AT) inflammation are the major causes of insulin resistance. Abnormal accumulation and activation of AT macrophages (ATMs) and abnormal activation of the TLR4-mediated immune responses within ATMs are the key characters of the chronic low-grade AT inflammation associated with insulin resistance. We have recently shown that GPR120 acts as a physiological receptor of omega-3 fatty acid in macrophages and adipocytes, which mediate potent anti-inflammatory and insulin-sensitizing effects. The important role that GPR120 has in the control of inflammation raises the possibility that targeting this receptor could have therapeutic potential in many inflammatory diseases including obesity and type 2 diabetes. In this review paper, we discuss omega-3 fatty acid-sensing GPR120 and highlight the potential outcomes of targeting this receptor in ameliorating disease.

肥胖是获得性胰岛素抵抗的主要原因,肥胖在美国的流行导致了2型糖尿病发病率的显著增加。脂肪细胞功能障碍和慢性低级别脂肪组织(AT)炎症是胰岛素抵抗的主要原因。AT巨噬细胞(ATMs)的异常积聚和激活以及ATMs内tlr4介导的免疫应答的异常激活是胰岛素抵抗相关的慢性低度AT炎症的关键特征。我们最近的研究表明,GPR120在巨噬细胞和脂肪细胞中作为omega-3脂肪酸的生理受体,介导有效的抗炎和胰岛素增敏作用。GPR120在炎症控制中的重要作用提高了靶向该受体可能在许多炎症性疾病(包括肥胖和2型糖尿病)中具有治疗潜力的可能性。在这篇综述文章中,我们讨论了omega-3脂肪酸传感GPR120,并强调了靶向该受体在改善疾病中的潜在结果。
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引用次数: 7
Peripheral actions of GPCRs in energy homeostasis: view from the Chair. gpcr在能量稳态中的外周作用:主席的观点。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.2
M Bouvier

The roles of G-protein-coupled receptors (GPCRs) in the control of food intake and energy expenditure are being increasingly recognized, and new drug candidates targeting these receptors are making their entry into the clinic. GPCRs exert their action along the various sites of regulation of energy homeostasis control including the central nervous system, the pancreas, the gut and fat cells. Exciting new data about GPCRs recognizing and mediating the effects of lipid mediators and concerning receptors for which no endogenous ligands have been identified yet open new exciting avenues for the validation of additional drug targets. In addition, recently developed paradigms around the concepts of cross-talk regulation and functional selectivity should lead to the development of drugs with improved therapeutic efficacy and reduced undesirable effects. Some of these promising discoveries are discussed in the present article and accompanying papers.

g蛋白偶联受体(gpcr)在控制食物摄入和能量消耗中的作用越来越被认识到,针对这些受体的新候选药物正在进入临床。GPCRs在能量稳态控制的各种调控位点发挥作用,包括中枢神经系统、胰腺、肠道和脂肪细胞。关于gpcr识别和介导脂质介质作用的令人兴奋的新数据,以及尚未确定内源性配体的受体,为验证其他药物靶点开辟了令人兴奋的新途径。此外,最近围绕串扰调节和功能选择性概念开发的范式应该会导致开发出具有提高治疗效果和减少不良反应的药物。本文和随附的论文讨论了其中一些有希望的发现。
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引用次数: 0
The class B G-protein-coupled GLP-1 receptor: an important target for the treatment of type-2 diabetes mellitus. B类g蛋白偶联GLP-1受体:治疗2型糖尿病的重要靶点
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.4
L J Miller, P M Sexton, M Dong, K G Harikumar

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone secreted from L cells in the distal small intestine and proximal colon after a meal that acts as an incretin to augment the insulin response, while also inhibiting glucagon and slowing gastric emptying. These characteristics of GLP-1, as well as its ability to reduce islet beta cell apoptosis and expand beta cell mass and its cardioprotective and neuroprotective effects, provide a broad spectrum of actions potentially useful for the management of type-2 diabetes mellitus. GLP-1 also has the added advantage of having its incretin effects dependent on the level of serum glucose, only acting in the presence of hyperglycaemia, and thereby preventing hypoglycemic responses. Although natural GLP-1 has a very short half-life, limiting its therapeutic usefulness, a variety of analogues and formulations have been developed to provide extended actions and to limit side effects. However, all of these peptides require parenteral administration. Potentially orally active small-molecule agonists acting at the GLP-1 receptor are also being developed, but have not yet been approved for clinical use. Recent insights into the molecular nature of the class B G-protein-coupled GLP-1 receptor has provided insights into the modes of binding these types of ligands, as well as providing opportunities for rational enhancement. The advantages and disadvantages of each of these agents and their possible clinical utility will be explored.

胰高血糖素样肽-1 (glucagon -like peptide-1, GLP-1)是小肠远端和结肠近端L细胞在餐后分泌的一种胃肠道激素,可作为肠促胰岛素增强胰岛素反应,同时抑制胰高血糖素,减缓胃排空。GLP-1的这些特性,以及其减少胰岛β细胞凋亡和扩大β细胞质量的能力,以及其心脏和神经保护作用,为2型糖尿病的治疗提供了广泛的可能有用的作用。GLP-1还有一个额外的优点,即它的促肠促胰岛素作用依赖于血清葡萄糖水平,仅在高血糖存在时起作用,从而防止低血糖反应。虽然天然GLP-1的半衰期很短,限制了其治疗作用,但各种类似物和制剂已被开发出来,以提供延长的作用并限制副作用。然而,所有这些多肽都需要肠外给药。作用于GLP-1受体的潜在口服活性小分子激动剂也正在开发中,但尚未批准临床使用。最近对B类g蛋白偶联GLP-1受体的分子性质的见解,提供了对这些类型配体结合模式的见解,并为合理增强提供了机会。我们将探讨每种药物的优缺点及其可能的临床应用。
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引用次数: 13
New horizons on the role of cannabinoid CB1 receptors in palatable food intake, obesity and related dysmetabolism. 大麻素CB1受体在美味食物摄入、肥胖和相关代谢障碍中的作用的新视野。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.8
L Cristino, L Palomba, V Di Marzo

Excessive consumption of high-energy, palatable food contributes to obesity, which results in the metabolic syndrome, heart disease, type-2 diabetes and death. Current knowledge on the function of the hypothalamus as the brain 'feeding centre' recognizes this region as the main regulator of body weight in the central nervous system. Because of their intrinsically fast and adaptive activities, feeding-controlling neural circuitries are endowed with synaptic plasticity modulated by neurotransmitters and hormones that act at different hierarchical levels of integration. In the hypothalamus, among the chemical mediators involved in this integration, endocannabinoids (eCBs) are ideal candidates for the fast (that is, non-genomic), stress-related fine-tuning of neuronal functions. In this article, we overview the role of the eCB system (ECS) in the control of energy intake, and particularly in the consumption of high-energy, palatable food, and discuss how such a role is affected in the brain by changes in the levels of feeding-regulated hormones, such as the adipose tissue-derived anorexigenic mediator leptin, as well as by high-fat diets. The understanding of the molecular mechanisms underlying the neuronal control of feeding behaviours by eCBs offers many potential opportunities for novel therapeutic approaches against obesity. Highlights of the latest advances in the development of strategies that minimize central ECS overactivity in 'western diet'-driven obesity are discussed.

过量食用高能量、美味的食物会导致肥胖,从而导致代谢综合征、心脏病、2型糖尿病和死亡。目前关于下丘脑作为大脑“进食中心”的功能的知识认为,该区域是中枢神经系统中体重的主要调节器。由于其固有的快速和适应性活动,进食控制神经回路被赋予突触可塑性,由不同层次整合水平的神经递质和激素调节。在下丘脑中,在参与这种整合的化学介质中,内源性大麻素(eCBs)是快速(即非基因组)、与压力相关的神经元功能微调的理想候选者。在这篇文章中,我们概述了eCB系统(ECS)在控制能量摄入中的作用,特别是在高能量、美味食物的消耗中,并讨论了这种作用是如何受到喂养调节激素水平变化的影响的,比如脂肪组织来源的厌食介质瘦素,以及高脂肪饮食。对脑脊液神经元控制摄食行为的分子机制的理解为肥胖的新治疗方法提供了许多潜在的机会。重点讨论了在“西方饮食”驱动型肥胖中减少中枢ECS过度活动的策略发展的最新进展。
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引用次数: 18
The physiological relevance of functional selectivity in dopamine signalling. 多巴胺信号功能选择性的生理相关性。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.3
N M Urs, M G Caron

We sought to determine the role of functionally selective dopamine (DA) signalling pathways (G protein or β-arrestin) in DA-dependent behaviours. Mice that were globally deficient for β-arrestins or mice deficient in GSK3β in D2 receptor (D2R)-expressing neurons were used to investigate the role of functional selectivity in DA-dependent behaviours such as locomotor activity and conditioned place preference (CPP). Wild-type or knockout mice were injected with drugs such as morphine and amphetamine, which are known to increase DA levels in the brain and to induce a hyper-locomotor response and CPP. Unlike β-arrestin1 (βarr1)-deficient mice, mice globally deficient for β-arrestin2 (βarr2) mount a reduced hyperlocomotor response to either morphine or amphetamine. However, mice deficient in GSK3β in D2R-expressing neurons show a significantly reduced locomotor response to only amphetamine but not morphine. Interestingly, all mice tested show a normal CPP response to either morphine or amphetamine. β-arrestin-mediated DA receptor signalling has an important role in the locomotor response, but not CPP, to drugs such as morphine and amphetamine, demonstrating a functional selectivity of DA-dependent behaviours in mice. It is likely that G-protein-dependent signalling through DA receptors mediates the CPP response.

我们试图确定功能选择性多巴胺(DA)信号通路(G蛋白或β-阻滞蛋白)在DA依赖行为中的作用。我们使用D2受体(D2R)表达神经元中β-抑制素缺失或GSK3β缺失的小鼠,研究功能选择性在da依赖行为(如运动活动和条件位置偏好(CPP))中的作用。野生型或基因敲除小鼠注射吗啡和安非他明等药物,这些药物已知会增加大脑中的DA水平,并诱导超运动反应和CPP。与β-arrestin1 (βarr1)缺失的小鼠不同,β-arrestin2 (βarr2)缺失的小鼠对吗啡或安非他明的过度运动反应减弱。然而,在表达d2r的神经元中缺乏GSK3β的小鼠,仅对安非他明而非吗啡的运动反应显著降低。有趣的是,所有接受测试的小鼠对吗啡或安非他明都表现出正常的CPP反应。β-抑制素介导的DA受体信号传导在小鼠对吗啡和安非他明等药物的运动反应中发挥重要作用,但在CPP中不起作用,这表明小鼠对DA依赖行为具有功能选择性。可能是g蛋白依赖的信号通过DA受体介导CPP反应。
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引用次数: 8
Central (mainly) actions of GPCRs in energy homeostasis/balance: view from the Chair. gpcr在能量稳态/平衡中的中心(主要)作用:主席的观点。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.7
N Gallo-Payet

To maintain a constant body weight, energy intake must equal energy expenditure; otherwise, there is a risk of overweight and obesity. The hypothalamus is one of the primary brain regions where multiple nutrient-related signals from peripheral and central sources converge and become integrated to regulate both short- and long-term nutritional states. The aim of the afternoon session of the 15th Annual International Symposium of the Laval University Obesity Research Chair held in Quebec City on 9 November 2012 was to present the most recent insights into the complex molecular mechanisms regulating food intake. The aims were to emphasize on the interaction between central and peripheral actions of some of the key players acting not only at the hypothalamic level but also at the periphery. Presentations were focused on melanocortin-3 receptor (MC3R) and melanin-concentrating hormone (MCH) as anorexigenic and orexigenic components of the hypothalamus, on endocannabinoid receptors, initially as a central neuromodulatory signal, and on glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) as peripheral signals. What becomes clear from these four presentations is that the regulation of food intake and energy homeostasis involves several overlapping pathways, and that we have only touched the tip of the iceberg. From the examples presented in this symposium, it could be expected that in the near future, in addition to a low-fat diet and exercise, a combination of appropriate peptides and small molecules is likely to become available to improve/facilitate the objectives of long-term maintenance of energy balance and body weight.

为了保持恒定的体重,能量摄入必须等于能量消耗;否则,就有超重和肥胖的风险。下丘脑是来自外周和中枢来源的多种营养相关信号汇聚并整合以调节短期和长期营养状态的主要脑区之一。2012年11月9日在魁北克市举行的拉瓦尔大学肥胖症研究主席第15届年度国际研讨会下午会议的目的是介绍对调节食物摄入的复杂分子机制的最新见解。目的是强调中枢和外周活动之间的相互作用,一些关键参与者不仅在下丘脑水平,而且在外周。报告集中在黑素皮质素-3受体(MC3R)和黑色素浓缩激素(MCH)作为下丘脑的厌氧和厌氧成分,内源性大麻素受体,最初作为中枢神经调节信号,胰高血糖素样肽-1 (GLP-1)和胃抑制多肽(GIP)作为外周信号。从这四篇演讲中,我们清楚地看到,食物摄入和能量平衡的调节涉及几个重叠的途径,而我们只触及了冰山一角。从本次研讨会的例子来看,可以预期在不久的将来,除了低脂饮食和运动外,合适的多肽和小分子的组合可能会改善/促进长期维持能量平衡和体重的目标。
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引用次数: 0
Unravelling the mysterious roles of melanocortin-3 receptors in metabolic homeostasis and obesity using mouse genetics. 利用小鼠遗传学揭示黑素皮质素-3受体在代谢稳态和肥胖中的神秘作用。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.10
C Girardet, K Begriche, A Ptitsyn, R A Koza, A A Butler

The central nervous melanocortin system maintains body mass and adiposity within a 'healthy' range by regulating satiety and metabolic homeostasis. Neural melanocortin-4 receptors (MC4R) modulate satiety signals and regulate autonomic outputs governing glucose and lipid metabolism in the periphery. The functions of melanocortin-3 receptors (MC3R) have been less well defined. We have observed that food anticipatory activity (FAA) is attenuated in Mc3r-/- mice housed in light:dark or constant dark conditions. Mc3r-/- mice subjected to the restricted feeding protocol that was used to induce FAA also developed insulin resistance, dyslipidaemia, impaired glucose tolerance and evidence of a cellular stress response in the liver. MC3Rs may thus function as modulators of oscillator systems that govern circadian rhythms, integrating signals from nutrient sensors to facilitate synchronizing peak foraging behaviour and metabolic efficiency with nutrient availability. To dissect the functions of MC3Rs expressed in hypothalamic and extra-hypothalamic structures, we inserted a 'lox-stop-lox' (TB) sequence into the Mc3r gene. Mc3r (TB/TB) mice recapitulate the phenotype reported for Mc3r-/- mice: increased adiposity, accelerated diet-induced obesity and attenuated FAA. The ventromedial hypothalamus exhibits high levels of Mc3r expression; however, restoring the expression of the LoxTB Mc3r allele in this nucleus did not restore FAA. However, a surprising outcome came from studies using Nestin-Cre to restore the expression of the LoxTB Mc3r allele in the nervous system. These data suggest that 'non-neural' MC3Rs have a role in the defence of body weight. Future studies examining the homeostatic functions of MC3Rs should therefore consider actions outside the central nervous system.

中枢神经黑素皮质素系统通过调节饱腹感和代谢稳态,将体重和肥胖维持在“健康”的范围内。神经黑素皮质素-4受体(MC4R)调节饱腹感信号并调节控制外周糖脂代谢的自主输出。黑素皮质素-3受体(MC3R)的功能尚未明确。我们观察到Mc3r-/-小鼠在光照:黑暗或持续黑暗条件下的食物预期活动(FAA)减弱。Mc3r-/-小鼠接受用于诱导FAA的限制喂养方案也出现胰岛素抵抗、血脂异常、糖耐量受损和肝脏细胞应激反应的证据。因此,MC3Rs可能作为控制昼夜节律的振荡器系统的调制器,整合来自营养传感器的信号,以促进峰值觅食行为和代谢效率与营养可用性的同步。为了剖析在下丘脑和下丘脑外结构中表达的MC3Rs的功能,我们在Mc3r基因中插入了一个“lox-stop-lox”(TB)序列。Mc3r (TB/TB)小鼠概括了Mc3r-/-小鼠的表型:肥胖增加,饮食诱导的肥胖加速和FAA减弱。下丘脑腹内侧显示Mc3r高水平表达;然而,恢复LoxTB Mc3r等位基因在该细胞核中的表达并没有恢复FAA。然而,使用nesting - cre恢复LoxTB Mc3r等位基因在神经系统中的表达的研究得出了一个令人惊讶的结果。这些数据表明,“非神经性”mc3r在保护体重方面发挥了作用。因此,未来研究MC3Rs的稳态功能应该考虑中枢神经系统外的作用。
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引用次数: 15
Coordinate control of adipose 'browning' and energy expenditure by β-adrenergic and natriuretic peptide signalling. 通过β-肾上腺素和利钠肽信号协调控制脂肪“褐变”和能量消耗。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.6
S Collins, R Sarzani, M Bordicchia

The catecholamines and the adrenergic receptors have been long known to be vital components in the regulation of fat cell metabolism. Whether in response to stress, cold temperature or diet, the β-adrenergic receptors (βARs) respond to epinephrine/norepinephrine to activate a signalling cascade that drives triglyceride hydrolysis to free fatty acids for use as fuel for skeletal and cardiac muscle work. The βARs also are well-established activators of brown fat for the conversion of substrate energy to generate heat from the oxidation of glucose and fatty acids. Long thought to be irrelevant to the biology of adult humans, the realization that there is indeed functional brown fat in humans has now created great interest and enthusiasm over the possibility that recruiting brown fat to target obesity and metabolic disease could represent a viable therapeutic option. Coupled with newer evidence that various stimuli independent of the βARs may also be able to increase active brown adipocytes, including the cardiac natriuretic peptides, it is an exciting time to be working in this area. This review will focus on the catecholamines and natriuretic peptides as cooperative actors in promoting fat metabolism, and will consider areas in need of further research.

儿茶酚胺和肾上腺素能受体长期以来一直被认为是调节脂肪细胞代谢的重要成分。无论是对压力、低温还是饮食的反应,β-肾上腺素能受体(βARs)对肾上腺素/去甲肾上腺素作出反应,激活信号级联,驱动甘油三酯水解为游离脂肪酸,作为骨骼和心肌工作的燃料。β ar也是棕色脂肪的激活剂,用于将底物能量转化为葡萄糖和脂肪酸氧化产生的热量。长期以来,人们一直认为棕色脂肪与成年人的生物学无关,但认识到人类确实存在功能性棕色脂肪,现在人们对利用棕色脂肪来治疗肥胖和代谢疾病的可能性产生了极大的兴趣和热情,这可能是一种可行的治疗选择。再加上新的证据表明,各种独立于β ar的刺激也可能增加活跃的棕色脂肪细胞,包括心脏利钠肽,这是一个令人兴奋的时刻,在这一领域的工作。本文就儿茶酚胺和利钠肽在促进脂肪代谢中的协同作用作一综述,并对有待进一步研究的领域作一展望。
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引用次数: 16
The melanin-concentrating hormone receptors: neuronal and non-neuronal functions. 黑色素浓缩激素受体:神经元和非神经元功能。
Pub Date : 2014-07-01 Epub Date: 2014-07-08 DOI: 10.1038/ijosup.2014.9
F Presse, G Conductier, C Rovere, J-L Nahon

Melanin-concentrating hormone (MCH) is a cyclic peptide highly conserved in vertebrates and was originally identified as a skin-paling factor in Teleosts. In fishes, MCH also participates in the regulation of the stress-response and feeding behaviour. Mammalian MCH is a hypothalamic neuropeptide that displays multiple functions, mostly controlling feeding behaviour and energy homeostasis. Transgenic mouse models and pharmacological studies have shown the importance of the MCH system as a potential target in the treatment of appetite disorders and obesity as well as anxiety and psychiatric diseases. Two G-protein-coupled receptors (GPCRs) binding MCH have been characterized so far. The first, named MCH-R1 and also called SLC1, was identified through reverse pharmacology strategies by several groups as a cognate receptor of MCH. This receptor is expressed at high levels in many brain areas of rodents and primates and is also expressed in peripheral organs, albeit at a lower rate. A second receptor, designated MCH-R2, exhibited 38% identity to MCH-R1 and was identified by sequence analysis of the human genome. Interestingly, although MCH-R2 orthologues were also found in fishes, dogs, ferrets and non-human primates, this MCH receptor gene appeared either lacking or non-functional in rodents and lagomorphs. Both receptors are class I GPCRs, whose main roles are to mediate the actions of peptides and neurotransmitters in the central nervous system. However, examples of action of MCH on neuronal and non-neuronal cells are emerging that illustrate novel MCH functions. In particular, the functionality of endogenously expressed MCH-R1 has been explored in human neuroblastoma cells, SK-N-SH and SH-SY5Y cells, and in non-neuronal cell types such as the ependymocytes. Indeed, we have identified mitogen-activated protein kinase (MAPK)-dependent or calcium-dependent signalling cascades that ultimately contributed to neurite outgrowth in neuroblastoma cells or to modulation of ciliary beating in ependymal cells. The putative role of MCH on cellular shaping and plasticity on one side and volume transmission on the other must be now considered.

黑色素浓缩激素(Melanin-concentrating hormone, MCH)是一种在脊椎动物中高度保守的环状肽,最初被确定为硬骨鱼的皮肤变白因子。在鱼类中,MCH还参与应激反应和摄食行为的调节。哺乳动物的MCH是一种具有多种功能的下丘脑神经肽,主要控制摄食行为和能量稳态。转基因小鼠模型和药理学研究表明,MCH系统在治疗食欲障碍、肥胖以及焦虑和精神疾病方面具有重要的潜在作用。目前已知两种g蛋白偶联受体(gpcr)与MCH结合。第一种被命名为MCH- r1,也被称为SLC1,通过反向药理学策略被几个小组鉴定为MCH的同源受体。这种受体在啮齿类动物和灵长类动物的许多脑区都有高水平的表达,在周围器官中也有表达,尽管表达率较低。第二个受体MCH-R2与MCH-R1的同源性为38%,通过人类基因组序列分析得到。有趣的是,尽管在鱼类、狗、雪貂和非人灵长类动物中也发现了MCH- r2同源基因,但这种MCH受体基因在啮齿动物和狐形动物中似乎缺乏或无功能。这两种受体都是一类gpcr,其主要作用是在中枢神经系统中介导多肽和神经递质的作用。然而,MCH对神经元和非神经元细胞的作用的例子正在出现,说明了MCH的新功能。特别是,内源性表达的MCH-R1在人神经母细胞瘤细胞、SK-N-SH和SH-SY5Y细胞以及室管膜细胞等非神经元细胞类型中的功能已经被探索。事实上,我们已经确定了丝裂原激活蛋白激酶(MAPK)依赖或钙依赖的信号级联,最终有助于神经母细胞瘤细胞的神经突生长或室管膜细胞纤毛跳动的调节。现在必须考虑到MCH对细胞形成和可塑性的作用,以及对体积传输的作用。
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引用次数: 24
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International journal of obesity supplements
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