Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss.
Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss.
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DOI：
10.7554/elife.09800
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发表时间：
2015-09-02
期刊：
影响因子：
7.7
通讯作者：
Sternson SM
中科院分区：
文献类型：
--
作者：
Henry FE;Sugino K;Tozer A;Branco T;Sternson SM
神经元中的分子和细胞过程对于感知和响应能量不足状态至关重要，例如在减肥期间。Agouti相关蛋白（AGRP）表达神经元是下丘脑的一个关键群体，在能量不足、食欲增加和体重增加时被激活。细胞类型特异性转录组学可用于识别抵消体重减轻的途径，在这里，我们报告了高质量的AGRP神经元基因表达谱，这些基因表达谱来自营养充足和缺乏食物的年轻成年小鼠。为了进行比较，我们还分析了表达Proopiomelanocortin （POMC）的神经元，这是一种抑制食欲和体重的混合种群。我们发现AGRP神经元比POMC神经元对能量不足更为敏感。此外，我们还确定了细胞类型特异性通路，包括内质网应激、昼夜节律信号、离子通道、神经肽和受体。结合验证和操纵这些途径的方法，这一资源极大地扩展了对体重神经元调节的分子洞察力，并可能有助于制定肥胖和饮食失调的治疗策略。DOI: http://dx.doi.org/10.7554/eLife.09800.001人类和其他动物必须获得足够的营养才能生存。因此，身体有几个系统并肩工作，以保持健康的体重，并确保摄入足够的食物来提供身体所需的能量。这些系统的问题会导致肥胖和其他饮食失调。大脑中某些类型的细胞在控制体重和食欲方面发挥着重要作用，尽管这些能力背后的基因和细胞机制尚不清楚。当动物被剥夺食物时，所谓的AGRP神经元会产生增加食欲的分子，使其更容易发胖。在减肥过程中，这些神经元也会经历结构变化，并增加它们的电活动。另一组被称为POMC神经元的细胞在动物被剥夺能量时变得不那么活跃。Henry、Sugino等人利用一种称为细胞类型特异性转录组学的技术，揭示了AGRP和POMC神经元中数百个基因的表达变化取决于小鼠是被喂饱还是被剥夺食物。与其他类型的脑细胞相比，食物剥夺对AGRP神经元中基因的影响也更多，而且AGRP神经元对食物摄入量的变化也比POMC神经元更敏感。在未来，这些基因表达数据和受基因影响的途径的知识可以帮助研究人员开发新的治疗肥胖和其他影响食欲的疾病的方法。Henry， Sugino等人随后绘制了这些基因表达的变化如何触发神经元中的分子“通路”，从而改变细胞的工作方式。这些影响细胞的许多部分，包括离子通道、转录因子、受体和分泌蛋白。此外，食物剥夺激活了AGRP神经元中保护细胞免受神经元活动升高引起的损伤和死亡的通路，也触发了增加体重的信号通路。在未来，这些基因表达数据和受基因影响的途径的知识可以帮助研究人员开发新的治疗肥胖和其他影响食欲的疾病的方法。DOI: http://dx.doi.org/10.7554/eLife.09800.002
Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. Agouti related protein (AGRP)-expressing neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed Proopiomelanocortin (POMC)-expressing neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders. DOI: http://dx.doi.org/10.7554/eLife.09800.001 Humans and other animals must get adequate nutrition in order to survive. As a result, the body has several systems that work side by side to maintain a healthy body weight and ensure that enough food gets eaten to provide the energy that the body needs. Problems with these systems can contribute towards obesity and other eating disorders. Certain types of cells in the brain play important roles in controlling weight and appetite, although the genes and cellular mechanisms that underlie these abilities are not well understood. When an animal is deprived of food, so-called AGRP neurons produce molecules that increase appetite and make it easier to gain weight. These neurons also go through structural changes and increase their electrical activity during weight loss. Another group of cells, called the POMC neurons, becomes less active when an animal is deprived of energy. Using a technique called cell type-specific transcriptomics, Henry, Sugino et al. have now revealed that the expression of hundreds of genes in AGRP and POMC neurons changes depending on whether mice are well fed or food deprived. Food deprivation also affects more genes in AGRP neurons than has been seen in other types of brain cell, and the AGRP neurons are also more sensitive to a change in food intake than POMC neurons. In the future, this gene expression data and knowledge of the pathways affected by the genes could help researchers to develop new treatments for obesity and other disorders that affect appetite. Henry, Sugino et al. then mapped how these changes in gene expression trigger molecular “pathways” in the neurons that alter how the cells work. These affect many parts of the cells, including ion channels, transcription factors, receptors, and secreted proteins. In addition, food deprivation activated pathways in AGRP neurons that protect the cells from damage and death caused by elevated neuron activity and also triggered signaling pathways that increase body weight. In the future, this gene expression data and knowledge of the pathways affected by the genes could help researchers to develop new treatments for obesity and other disorders that affect appetite. DOI: http://dx.doi.org/10.7554/eLife.09800.002