下丘脑的代谢与能量平衡调控功能研究进展

下丘脑是调控代谢稳态与能量平衡的关键脑区,对摄食、营养素代谢、机体水平衡、基础代谢、体温、生理节律等代谢相关功能发挥核心调控作用,维系机体异化作用与同化作用平衡。近年来,随着神经科学技术的发展,下丘脑参与代谢调控的神经核团、神经通路、及其机理被深入研究,并揭示出一系列重要的新发现。这些新发现,对深入理解肥胖及相关代谢疾病发病机制具重要意义。值得注意的是,下丘脑功能失调,与肥胖、二型糖尿病等代谢疾病发病密切相关。本文综述近年来有关下丘脑调控代谢和能量平衡研究进展,以期深入了解下丘脑调控代谢和能量平衡的神经与分子机制,并为相关疾病的诊疗提供新信息。     

神经干细胞向神经元分化调控的研究进展

神经干细胞是一类具有分裂潜能和自更新能力的母细胞,它可以通过对称分裂和不对称分裂方式产生神经组织的各类细胞,包括神经元、星形胶质细胞和少突胶质细胞。中枢神经系统受到损伤后,神经元和胶质细胞的损伤导致了临床症状,内源性神经干细胞的修复作用不大,原因是干细胞的数量有限,微环境的不允许。移植的神经干细胞进入体内后,由于受到多种因素的影响,常保持未分化状态或大部分分化为胶质细胞。神经干细胞向神经元分化的调控机制及其影响因素直接决定神经干细胞源性神经元的比例和神经元之间功能性突触的数量。现就其研究进展做一综述。     

弧菌几丁质降解代谢及调控机理的研究进展

对近年来在弧菌中几丁质降解代谢的主要过程及调控机理方面的研究进行了综述,指出弧菌降解几丁质主要分为3个步骤,几丁质的水解、几丁寡糖和N-乙酰基葡萄糖胺的运输、几丁二糖和N-乙酰基葡萄糖胺-6-磷酸的进一步降解等,且此过程的许多环节均受到二元信号传导系统的调控。     

长链非编码RNA调控脂肪发育与代谢研究进展

长链非编码RNA(long noncoding RNA,lncRNA)是一种广泛存在于动植物中、长度大于200个核苷酸且不能编码蛋白的RNA。近年来,随着高通量基因组测序技术的不断发展,研究者们对lncRNA的关注度越来越高,通过对lncRNA的深入研究,证实其在细胞分化、表观遗传、细胞周期调控等众多生命活动中发挥重要作用,并且很多疾病的发生、发展过程都与之相关。借助于高通量测序或芯片技术,已经证实许多lncRNA与脂肪组织的生成、发育和代谢调控有关,在脂肪发育的过程中起着重要的作用。通过对脂肪发育相关lncRNA的研究可以更好地了解脂肪的发育、代谢过程,同时为代谢疾病的临床治疗提供新的方法。基于此,对lncRNA作用模式、调控脂肪发育以及其对肥胖相关代谢疾病的影响等研究展开综述,以期为脂肪发育与代谢研究提供理论指导。     

肠道微生物及其代谢产物与宿主脂质代谢研究进展

近年来,肠道微生物与宿主脂质代谢研究受到国内外的广泛关注.首先,肠道微生物多样性和组成在脂肪代谢紊乱动物模型、肥胖患者中均发生显著改变,而利用粪菌移植、益生菌以及营养干预重塑肠道菌群结构可以调控宿主脂质代谢.本文重点介绍了肠道微生物与宿主脂代谢的联系,并从短链脂肪酸、胆汁酸、氨基酸、内毒素和微生物节律等方面探讨了肠道微...     

Neuritin对神经元作用的研究进展

Neuritin作为神经营养因子,可促进神经细胞树突和轴突的生长和分支,以及调节神经元回路的形成,在神经再生和可塑性中起着重要作用.它由一条编码糖基磷脂酰肌醇锚定的糖蛋白基因编码,表达产物主要分布于神经系统中,其中以齿状回最高,其次为海马,大脑皮层和小脑.Neuritin作为神经活动和神经营养素发挥作用的共同下游因子,在促进突触成热、防止神经细胞凋亡和保护运动神经元等方面具有重要作用.本文就Neuritin的生物学特性及其在神经再生领域的研究做一综述.     

神经元形态重建工具的研究进展

近年来,分子标记和显微光学成像技术的系列突破,使得单细胞分辨的全脑尺度神经群落成像成为现实.然而,现有神经元形态重建工具的发展速度远远滞后于海量数据的产生速度,难以满足现阶段成像数据的分析需求.在此背景下,我们首先分析了神经元形态重建工具发展滞后的原因,简述现有半自动和全自动神经元形态重建工具的特点和最新发展,并结合现有工具的特点分析其向高通量、高准确度重建工具发展时面临的挑战.最后,我们对未来形态重建工具的发展趋势及应用前景做出展望.     

固有淋巴细胞在脂质代谢中的研究进展

由于世界范围内营养条件和生活方式的变化,肥胖及其相关的代谢性疾病已成为当前威胁人类健康的重要因素之一.在能量摄取和消耗以及体内脂肪储存、分解和脂肪组织重塑的研究中,人们逐渐认识到脂质过量及异位堆积将导致代谢组织处于慢性炎症状态,这开启了肥胖相关组织炎症研究的新方向.固有淋巴细胞(innate lymphoid cell...     

胆汁酸对代谢性疾病的调控

胆汁酸作为一种信号分子通过激活肝、肠道和外周组织中的胆汁酸受体影响体内葡萄糖和脂质的代谢平衡,对于调节肥胖、2型糖尿病和非酒精性脂肪肝等代谢性疾病具有非常重要的意义。胆汁酸与相应核受体,如法尼醇X受体(farnesoid X receptor, FXR)和Takeda G蛋白偶联受体5 (Takeda G protein-coupled receptor 5,TGR5)的相互作用影响了这些代谢性疾病。FXR主要通过影响胆汁酸的合成及转运对非酒精性脂肪肝发挥作用,TGR5则是间接增加褐色脂肪组织中的生热作用,改善肥胖和2型糖尿病。这些调控机制的研究是非常必要的。本文综述了胆汁酸代谢及其对代谢性疾病调控的分子机制的研究进展,以期为科研工作者提供一定的参考。     

昼夜节律钟调控代谢的研究进展

生理和行为的昼夜节律性调控对健康生活是必需的。越来越多的流行病学和遗传学证据显示昼夜节律的破坏与代谢紊乱性疾病相关联。在分子水平上,昼夜节律受到时钟蛋白组成的转录一翻译负反馈环的调控。时钟蛋白通过以下两种途径调节代谢：首先,时钟蛋白作为转录因子直接调节一些代谢关键步骤的限速酶和代谢相关核受体的表达,其次作为代谢相关核受体的辅调节因子来激活或抑制其转录活性。虽然时钟蛋白对代谢途径的调节导致代谢物水平呈昼夜节律振荡,但是产生的代谢物反过来又可以影响昼夜节律钟基因的表达,进而影响昼夜节律钟。深入研究昼夜节律钟与代谢的交互调节可能为治疗某些代谢紊乱性疾病提供新的治疗方案。     

NPY/AgRP neurons are not essential for feeding responses to glucoprivation

Animals respond to hypoglycemia by eating and by stimulating gluconeogenesis. These responses to glucose deprivation are initiated by glucose-sensing neurons in the brain, but the neural circuits that control feeding behavior are not well established. Neurons in the arcuate region of the hypothalamus that express neuropeptide Y (NPY) and agouti-related protein (AgRP) have been implicated in mediating the feeding response to glucoprivation. We devised a method to selectively ablate these neurons in neonatal mice and then tested adult mice for their feeding responses to fasting, mild hypoglycemia, 2-deoxy-d-glucose and a ghrelin receptor agonist. Whereas the feeding response to the ghrelin receptor agonist was completely abrogated, the feeding response to glucoprivation was normal. The feeding response after a fast was attenuated when standard chow was available but normal with more palatable solid or liquid diet. We conclude that NPY/AgRP neurons are not necessary for generating or mediating the orexigenic response to glucose deficiency, but they are essential for the feeding response to ghrelin and refeeding on standard chow after a fast.     

Rutecarpine ameliorates bodyweight gain through the inhibition of orexigenic neuropeptides NPY and AgRP in mice

Orexigenic neuropeptides NPY and AgRP play major roles in feeding and are closely related to obesity and diabetic metabolic syndrome. This study explored the inhibitory effect of rutecarpine on feeding and obesity in high-fat-diet-induced (C57BL/6) and leptin-deficient (ob/ob) obese mice. Both mice strains developed obesity, but the obesity was inhibited by the reduced food intake resulting from rutecarpine treatment (0.01%, p < 0.01). Blood cholesterol, non-fasting glucose, insulin, and leptin levels were reduced, compared with the control group. Rutecarpine inhibited the expression of NPY and AgRP in the arcuate nucleus (ARC) of the hypothalamus and suppressed the expression of both neuropeptides in N29-4 neuronal cells. These results indicate that rutecarpine ameliorates obesity by inhibiting food intake, which involves inhibited expression of the orexigenic neuropeptides NPY and AgRP.     

Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance

Macroautophagy is a lysosomal degradative pathway that maintains cellular homeostasis by turning over cellular components. Here we demonstrate a role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons in the regulation of food intake and energy balance. We show that starvation-induced hypothalamic autophagy mobilizes neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn regulate AgRP levels. The functional consequences of inhibiting autophagy are the failure to upregulate AgRP in response to starvation, and constitutive increases in hypothalamic levels of pro-opiomelanocortin and its cleavage product α-melanocyte-stimulating hormone that typically contribute to a lean phenotype. We propose a conceptual framework for considering how autophagy-regulated lipid metabolism within hypothalamic neurons may modulate neuropeptide levels to have immediate effects on food intake, as well as long-term effects on energy homeostasis. Regulation of hypothalamic autophagy could become an effective intervention in conditions such as obesity and the metabolic syndrome.     

AgRP neurons: a switch between peripheral carbohydrate and lipid utilization

EMBO J (2012) 31 22, 4276–4288 doi:10.1038/emboj.2012.250; published online September182012AgRP/NPY neurons are critical regulators of body weight and food intake. Concordant with their orexigenic effects, it is expected that AgRP ablation leads to the appearance of a lean phenotype. In the current issue of The EMBO Journal, Joly-Amado et al (2012) describe an obese phenotype in a model of AgRP-ablated mice, and link it to a shift in metabolic profile in efferent tissues such as the liver, muscle and pancreas.Hypothalamic AgRP/NPY neurons are known to play a key role in the regulation of body weight and food intake. With the advent of ‘toxin-receptor mediated cell knockout'' technology, several reports have tried to address the physiological relevance of this set of neurons. The ablation of Agrp-expressing neurons has different consequences depending on the age of the mice. Thus, in the neonatal stage, temporal deletion of AgRP neurons by diphtheria toxin (DT) injection has no major effects on energy balance (Luquet et al, 2005, 2007). However, in adult mice, as expected due to the potent orexigenic role of AgRP neurons, DT administration to these AgRP^DTR mice promotes a huge reduction in body weight and food intake in a short time (Bewick et al, 2005; Gropp et al, 2005; Luquet et al, 2005), which can even lead to starvation (Luquet et al, 2005). It has been hypothesized that the absence of effect in the neonates could be due to ‘compensatory mechanisms'' developed during the neonatal stage, when the neurocircuitry is not fully formed (Luquet et al, 2005). It has been shown that DT injection to adult mice, which have been previously treated with DT during the neonatal stage, does not have the same drastic effect as seen in starvation-induced DT treatment (Luquet et al, 2005). In this issue of The EMBO Journal, Joly-Amado et al (2012) report an increase in feeding efficiency in 3-month-old AgRP^DTR mice after DT injection during the neonatal stage. This change in feeding efficiency leads to an obese phenotype related to a decrease in locomotor activity. These results, contrary to those expected due to the orexigenic function of AgRP neurons, provide clues about the existence of a ‘compensatory mechanism''. Furthermore, in this study, the development of obesity is concomitant with an increase in fat depot weight.It is known that AgRP released from the AgRP/NPY neurons in the hypothalamus acts like an endogenous inhibitor of melanocortin receptors (MCRs) in the melanocortin system (Cone 2005). AgRP antagonizes the effects of POMC cleavage subproducts (e.g., α-msh) on these receptors to affect energy balance. It has been reported by Nogueiras et al (2007) that central manipulation of MCRs (using inhibitors or agonists) is able to control adiposity by modifying lipogenesis in WAT. Moreover, they found that hypothalamic MCRs act like a switch between carbohydrate and fat utilization: the blockade of MCRs decreases the percentage of fat utilized (Nogueiras et al, 2007). In the current issue, Joly-Amado et al (2012) describe changes in the same direction as found in this previous study; they report evidence of AgRP/NPY neuron involvement in the control of nutrient partitioning and lipid metabolism in peripheral tissues, in agreement with another report that demonstrated the importance of Sirt1 in AgRP neurons to modulate substrate utilization during fasting (Dietrich et al, 2010). The AgRP^DTR mice used in this study show a shift in substrate utilization. AgRP deficiency stimulates lipid utilization, that is, these mice obtain energy from stored fat. Despite this shift in metabolic profile, adult AgRP^DTR mice present more adiposity than controls. This can be explained by the fact that these mice show a potent increase in lipogenesis and triglyceride (TG) content in the liver. Post-pandrial plasma TG levels are raised, but they are normalized by fasting, providing evidence that the peripheral tissues of these AgRP-ablated mice obtain the energy required to maintain their functions from lipids. Furthermore, the authors describe a ‘paradoxical benefit'' in HFD-exposed mice. These animals are protected against the effects of HFD—their body weight and fat content are indistinguishable from wild-type mice, probably due to the fact that the mice utilize the excess fat found in the diet for energy.To investigate the cause of this increase in fat utilization, the authors looked into the possibility that the muscles use TG as fuel. They uncovered different results between oxidative (soleus) and fast glycolytic (white gastrocnemius) muscles. The former showed an increase in lipid utilization correlated with a decrease in the maximal OXPHOS complex I respiration rate. No changes were found in the latter. Taken together, these results indicate that the ability to oxidize lipids to obtain energy is ameliorated in the oxidative muscles of adult AgRP-ablated mice.Joly-Amado et al (2012) address the question about how the hypothalamic AgRP/NPY neurons can affect peripheral tissues. It is well known that the autonomic nervous system connects hypothalamic areas with different tissues (Nogueiras et al, 2007). Coinciding with previous studies that examined the sympathetic nervous system (SNS), the main mediator between the hypothalamus and WAT (Nogueiras et al, 2007), the current authors found that the SNS also mediates the response of the efferent tissues. They show that all of the effects described in liver, muscle and pancreas are dependent upon the SNS outflow from the hypothalamus.AgRP/NPY neurons also release γ-aminobutyric acid (GABA; Horvath et al, 1997). It has been demonstrated that GABA is necessary for the normal regulation of body weight (Tong et al, 2008). Constitutive inactivation of Vgat in AgRP neurons provokes body weight loss associated with an increase in locomotor activity (Tong et al, 2008). It has been reported that bretazenil (GABA agonist) replacement in adult AgRP^DTR mice after DT injection rescues the anorexic phenotype and minimizes changes in body weight and food intake (Wu et al, 2009). Furthermore, that study showed that bretazenil administration solely into the parabrachial nucleus is enough to prevent the anorexia. Joly-Amado et al (2012), following the same strategy as in previous reports, investigated the role of GABA in the phenotype reported. They found that subcutaneous bretazenil treatment rescues the obese phenotype in adult AgRP^DTR mice, increasing the RQ, which means an increase in carbohydrate utilization, and significantly decreasing the body fat content, thus emphasizing the importance of GABA release by the AgRP/NPY neurons to modulate energy balance.In summary (see Figure 1), Joly-Amado et al (2012) in a series of elegant experiments describe a novel phenotype observed in a mouse model of neonatal depletion of AgRP neurons. They link the obese phenotype observed in these mice with an increase in lipogenesis in the liver and an increase in lipid utilization by oxidative muscles. Furthermore, the authors show that these changes in the lipid profile of the peripheral tissues are due to AgRP ablation and are mediated by the SNS, and are not a consequence of adiposity in these mice. This study provides more clues about the existence of a ‘compensatory mechanism'' developed during the postnatal period. In spite of this, the mice are still sensitive to AgRP and GABA treatment. It is apparent that more effort is required to completely and comprehensively elucidate and understand the exact mechanism by which this model of AgRP-ablated mice become obese in adulthood.Open in a separate windowFigure 1AgRP neurons are essential for normal energy homeostasis. AgRP neurons play a critical role in the regulation of energy balance. Manipulation of these hypothalamic neurons causes changes in the normal phenotype. Joly-Amado et al (2012) describe that AgRP deletion in the neonatal stage brings about the appearance of an obese phenotype in adulthood. AgRP ablation promotes changes in efferent tissues that lead to an increase in adiposity.     

Third ventricular coinjection of subthreshold doses of NPY and AgRP stimulate food hoarding and intake and neural activation

We previously demonstrated that 3rd ventricular (3V) neuropeptide Y (NPY) or agouti-related protein (AgRP) injection potently stimulates food foraging/hoarding/intake in Siberian hamsters. Because NPY and AgRP are highly colocalized in arcuate nucleus neurons in this and other species, we tested whether subthreshold doses of NPY and AgRP coinjected into the 3V stimulates food foraging, hoarding, and intake, and/or neural activation [c-Fos immunoreactivity (c-Fos-ir)] in hamsters housed in a foraging/hoarding apparatus. In the behavioral experiment, each hamster received four 3V treatments by using subthreshold doses of NPY and AgRP for all behaviors: 1) NPY, 2) AgRP, 3) NPY+AgRP, and 4) saline with a 7-day washout period between treatments. Food foraging, intake, and hoarding were measured 1, 2, 4, and 24 h and 2 and 3 days postinjection. Only when NPY and AgRP were coinjected was food intake and hoarding increased. After identical treatment in separate animals, c-Fos-ir was assessed at 90 min and 14 h postinjection, times when food intake (0-1 h) and hoarding (4-24 h) were uniquely stimulated. c-Fos-ir was increased in several hypothalamic nuclei previously shown to be involved in ingestive behaviors and the central nucleus of the amygdala (CeA), but only in NPY+AgRP-treated animals (90 min and 14 h: magno- and parvocellular regions of the hypothalamic paraventricular nucleus and perifornical area; 14 h only: CeA and sub-zona incerta). These results suggest that NPY and AgRP interact to stimulate food hoarding and intake at distinct times, perhaps released as a cocktail naturally with food deprivation to stimulate these behaviors.     

AgRP Neurons Require Carnitine Acetyltransferase to Regulate Metabolic Flexibility and Peripheral Nutrient Partitioning

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FoxO1 target Gpr17 activates AgRP neurons to regulate food intake

Hypothalamic neurons expressing Agouti-related peptide (AgRP) are critical for initiating food intake, but druggable biochemical pathways that control this response remain elusive. Thus, genetic ablation of insulin or leptin signaling in AgRP neurons is predicted to reduce satiety but fails to do so. FoxO1 is a shared mediator of both pathways, and its inhibition is required to induce satiety. Accordingly, FoxO1 ablation in AgRP neurons of mice results in reduced food intake, leanness, improved glucose homeostasis, and increased sensitivity to insulin and leptin. Expression profiling of flow-sorted FoxO1-deficient AgRP neurons identifies G-protein-coupled receptor Gpr17 as a FoxO1 target whose expression is regulated by nutritional status. Intracerebroventricular injection of Gpr17 agonists induces food intake, whereas Gpr17 antagonist cangrelor curtails it. These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity.     

Metabolic state signalling through central hypocretin/orexin neurons

Hypothalamic neurons that produce the peptide transmitters hypocretins/orexins have attracted much recent attention. They provide direct and predominantly excitatory inputs to all major brain areas except the cerebellum, with the net effect of stimulating wakefulness and arousal. These inputs are essential for generating sustained wakefulness in mammals, and defects in hypocretin signalling result in narcolepsy. In addition, new roles for hypocretins/orexins are emerging in reward-seeking, learning, and memory. Recent studies also indicate that hypocretin/orexin neurons can alter their intrinsic electrical activity according to ambient fluctuations in the levels of nutrients and appetite-regulating hormones. These intriguing electrical responses are perhaps the strongest candidates to date for the elusive neural correlates of after-meal sleepiness and hunger-induced wakefulness. Hypocretin/orexin neurons may thus directly translate rises and falls in body energy levels into different states of consciousness.