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Jessica Houtz Guey-Ying Liao Juan Ji An Baoji Xu 《Proceedings of the National Academy of Sciences of the United States of America》2021,118(4)
Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-fexpressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkB neurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkB neurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkB neurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkB neurons that regulate food intake or thermogenesis. Activation of DMHTrkB neurons projecting to the raphe pallidus (RPa) stimulates thermogenesis and increased energy expenditure, whereas DMHTrkB neurons that send collaterals to the paraventricular hypothalamus (PVH) and preoptic area (POA) inhibit feeding. Together, our findings provide evidence that DMHTrkB neuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkB neuronal activity on food intake and thermogenesis.Impairments in energy homeostasis resulting from the compound effects of overeating and sedentary lifestyles have led to a profound increase in the rate of obesity around the world (1). Therapeutic strategies aimed at combating obesity by increasing energy expenditure or decreasing appetite have commonly failed due to counterregulatory mechanisms (2) and adverse side effects on cardiovascular physiology (3–5). To achieve safe and sustained weight loss, it will be essential to understand the mechanisms that govern and coordinate discrete physiological processes that contribute to energy homeostasis.Adaptive thermogenesis is the process by which energy is converted into heat and occurs primarily in brown adipose tissue (BAT) in response to environmental cues (6). BAT has a particularly high capacity for dissipating energy from fat and thus represents an important component of energy homeostasis. The dorsomedial hypothalamus (DMH) in the brain is centrally positioned in an established thermoregulatory neurocircuit, receiving inputs from the preoptic area (POA) (7–9) and sending excitatory projections to preautonomic neurons in the raphe pallidus (RPa) (10–13) that promote sympathetic activity in BAT, leading to increased thermogenesis. Direct chemical stimulation of the DMH (14) or activation of select populations of thermogenic DMH neurons (9, 11, 12, 15) leads to increased body temperature and energy expenditure but also significantly increases heart rate and blood pressure (12, 13, 15, 16). An inability to target increased sympathetic tone specifically in BAT without affecting other target tissues has greatly hampered strategies to treat obesity by targeting thermogenesis (4, 5).In addition to its influence on energy expenditure, the DMH also represents an important brain region in the regulation of feeding (17–19). Lesioning studies support an orexigenic role for the DMH (17), which can promote food intake through inhibitory projections to either the paraventricular hypothalamus (PVH) (18) or the arcuate nucleus (ARC) (20). Despite these early findings, evidence has also emerged that demonstrates the importance of anorexigenic populations of DMH neurons (19, 21, 22). We previously established that the activity of DMH neurons expressing the neurotrophin receptor TrkB (DMHTrkB) is important for regulating feeding, showing that activation of DMHTrkB neurons suppresses feeding and that deletion of the TrkB-encoding Ntrk2 gene in the DMH results in hyperphagia and obesity (21). Furthermore, humans with mutations in the TrkB-encoding NTRK2 gene exhibit severe obesity and impaired thermoregulation (23). However, it is unclear whether activation of DMHTrkB neurons has a direct influence on adaptive thermogenesis. Additionally, the neurocircuitry through which DMHTrkB neurons govern feeding or energy expenditure is unknown.Here, we demonstrate that DMHTrkB neuronal activity potently promotes energy expenditure by elevating thermogenesis and physical activity with a notable lack of influence on heart rate and blood pressure. We further reveal that DMHTrkB neurons send diverging projections to the RPa or the POA and PVH to differentially regulate energy expenditure and food intake, respectively. 相似文献
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Different cathode materials have different surface chemical components and machining capacities, which may finally result in different machining quality and machining efficiency of workpieces. In this paper, in order to investigate the influence of cathode materials on the electrochemical machining of thin-walled workpiece made of 304 stainless steel, five cylindrical electrodes are used as the target working cathodes of electrochemical machining to conduct experiments and research, including 45# steel, 304 stainless steel, aluminum alloy 6061, brass H62, and tungsten steel YK15. The stray current corrosion, taper, and material removal rate were used as the criteria to evaluate the drilling quality of efficiency of a thin-walled workpiece made of 304 stainless steel. The research results show that from the perspectives of stray current corrosion and taper, aluminum alloy 6061 is an optimal tool cathode, which should be used in the electrochemical machining of thin-walled workpieces made of 304 stainless steel; on the aspect of material removal rate, the 45# steel, 304 stainless steel, and aluminum alloy 6061 present close material removal rates, all of which are higher than that of brass H62 and tungsten steel YK15. Based on comprehensive consideration of both machining quality and machining efficiency, the aluminum alloy 6061 is the best option as the cathode tool in the electrochemical machining of thin-walled workpieces made of 304 stainless steel. 相似文献
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目的:通过观察腰椎小关节退变的CT、常规MRI及脂肪抑制序列的影像表现,进一步提高临床对椎小关节退变的认识.方法:回顾性分析538例腰椎小关节退变的影像学资料,运用x2检验对其每项影像学征象的CT、常规MRI及脂肪抑制序列检查结果进行统计学分析.结果:脂肪抑制序列显示关节滑膜的炎性改变优于CT和常规MRI,MRI对关节面软骨的观察优于CT(P<0.05);而CT观察骨性关节面及关节下骨质退变、关节腔真空征和伴发征象有明显优势(P<0.05);但对于骨质增生引起的椎小关节改变三者无明显统计学差异(P>0.05).结论:对于早期或慢性期急性发作的椎小关节退变患者,应首选MRI检查并加扫脂肪抑制序列;对于慢性期或需要手术的患者,应首选CT检查. 相似文献
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孕妇创伤性颅脑损伤临床特点与治疗 总被引:1,自引:0,他引:1
为提高孕妇颅脑损伤的救治水平,作者对22例孕妇颅脑损伤的临床资料进行分析,并观察东莨菪碱治疗作用。结果表明,脑挫裂伤合并脑内灶性出血多见(14/22),颅内血肿发生率低(8/22)。东莨菪碱对高颅压患者具有一定的降颅压作用。本组9例开颅手术,13例保守治疗。随访:2例轻残,20例治愈;婴、幼儿发育正常。结论:孕妇颅脑损伤及时正确处理,不影响正常妊娠。东莨菪碱尤其适用于妊娠高血压合并脑外伤患者。 相似文献
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全反式维甲酸(ATRA)也叫做视黄酸、维生素甲酸,是维生素A主要的生物活性形式,迄今为止ATRA在急性早幼粒细胞白血病(APL)中的应用已超过20年,并仍为APL治疗的标准方案。随着研究的不断深入,ATRA被广泛应用于甲状腺癌、肺癌、胃癌、卡波西氏肉瘤、卵巢癌、膀胱癌、神经母细胞瘤,等肿瘤的治疗中,且正逐步延伸至更多肿瘤的分化治疗。ATRA通过与核维甲酸受体(RAR)或维甲类X受体(RXR)结合并作用于维甲酸反应原件(RARE)从而调节基因的表达,在维持细胞稳态、调节细胞周期、信号转导、转录和翻译、调控肿瘤细胞的生长并促使其凋亡等发面发挥着重要的作用。肝脏是维生素A代谢的主要场所,相关研究显示,ATRA可通过调控相关蛋白(包括chemerin、信号蛋白Smad2/3、IGFBP-3等)以及遗传物质的表达,广泛参与肝炎、肝纤维化以及肝细胞癌的增殖、侵袭、凋亡等生物学过程。此外,ATRA可通过上调chemerin的表达来促进非酒精性脂肪性肝病的进展。肝星状细胞(HSC)也称为窦周细胞,是参与肝纤维化的主要细胞类型,当肝脏受损时,HSC可以转变为激活状态,活化的HSC通过分泌I型胶原蛋白(COL1α1)和α-平滑肌肌动蛋白(α-SMA),导致肝纤维化,而ATRA的活性形式维生素A可逆转HSC的激活和肝纤维化。一方面,Wnt信号通路通过激活HSC参与肝纤维化的形成,而ATRA可通过诱导RORα磷酸化,抑制Wnt/β-catenin的信号传递从而抑制肝纤维化的发生;另一方面,ATRA通过抑制TGF-β1/Smad信号通路的表达,从而发挥其抗肝纤维化作用。本文从多个途径阐述了ATRA抑制肝癌细胞的增殖并诱导其发生凋亡的机理,其中包括ATRA抑制Bcl-2和Bcl-x蛋白的表达从而诱导细胞发生凋亡的一系列过程,或直接充当诱导分化剂,诱导肝癌细胞发生凋亡的过程。此外,ATRA可通过调控相关遗传物质的表达来调节肝癌细胞的增值,其中包括通过抑制胰岛素样生长因子和促进维甲酸诱导基因1甲基化来抑制肝细胞癌的增值等。ATRA在肝癌中的应用是近几年才被初步认识的,目前,关于ATRA与肝脏疾病的关系尚无系统的认识,在肝癌中的具体调控机制有待进一步研究。充分认识ATRA与肝脏疾病的关系及其涉及的相关分子机制,可为肝病(非酒精性脂肪性肝病、肝纤维化、肝细胞癌等疾病)的临床诊疗提供新的策略和方向。 相似文献
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立体定向毁损杏仁核簇不同亚核团和扣带回前区治疗难治性精神分裂症 总被引:4,自引:1,他引:3
采用CRW立体定向仪和PICKER螺旋CT定位,用RADONICS毁损仪毁损杏仁核不同亚核团和扣带回前部治疗精神分裂症35例,并进行了一年的随访。以临床疗效总评量表(CGI)评定疗效标准为指标,评定病人疗效,旨在探讨立体定向毁损杏仁核不同亚核团和扣带回治疗难治性精神分裂症的可行性和疗效。用WEISS量表对35例病人手术前后的智力进行评定,总疗效评定结果:显著进步21例,进步8例,稍进步5例,无变化1例,无恶化者;手术后病人的智力未见明显损害。结果提示,根据精神分裂症患者的症状选择性地毁损杏仁核的不同亚核团可提高手术治疗的效果。 相似文献
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杏仁核亚核群毁损对PCP模型大鼠行为和递质的影响 总被引:3,自引:0,他引:3
目的探讨杏仁核亚核群毁损后五氯苯酚(pentachlorophenol,PCP)模型大鼠行为和前额叶单胺类递质含量的变化,为立体定向技术治疗精神病提供参考。方法经腹腔注射PCP制作精神分裂症动物模型,立体定向电极毁损大鼠杏仁核,对其刻板行为进行评分,应用高效液相色谱分析系统检测前额叶多巴胺(DA)、5-羟色胺(5-HT)和去甲肾上腺素(NE)的含量。结果杏仁核内侧核群毁损能减轻PCP模型大鼠的刻板行为和社会行为,与假毁损组之间具有非常显著性差别(P<0.001)。毁损组前额叶DA含量低于假毁损组(P <0.05),5-HT和NE含量均高于假毁损组(P<0.05)。结论PCP模型大鼠前额叶DA含量增高,5-HT和NE含量下降。立体定向毁损杏仁核内侧核群能够改变前额叶单胺类递质的水平,改善模型大鼠精神分裂症症状。 相似文献