Neurobiology for the sex differences in energy balance

能量平衡性别差异的神经生物学

• 批准号: 10374807
• 负责人: YONG XU
• 金额: $ 35.27万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374807
• 关键词: Action Potentials; Body Weight; Brain; Calcium-Activated Potassium Channel; Data; Diet; Equilibrium; Estrogens; Female; Gene Expression; Genes; Gonadal Steroid Hormones; Homeostasis; Hypothalamic structure; Maintenance; Mediating; Mediator of activation protein; Modeling; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Neurobiology; Neurons; Obesity; POMC gene; Phenotype; Physiological; Play; Population; Pro-Opiomelanocortin; Regulation; Role; Sex Differences; Signal Transduction; Synapses; Testing; Testosterone; Thinness; Weight; energy balance; feeding; male; obesogenic; receptor; relating to nervous system; response; sex; sexual dimorphism; transcription factor; transcriptome

Sexual dimorphism exists in body weight balance, but underlying mechanisms remain elusive. We screened a number of neural populations that are known to play key roles in the regulation of energy homeostasis, and found that hypothalamic neurons expressing pro-opiomelanocortin (POMC) display sex differences in two fundamental functions: (1) expressing the Pomc gene and (2) firing action potentials. In particular, female POMC neurons express more Pomc gene and firing more frequently than male POMC neurons. Mechanisms for this sexual dimorphism are not clear and little is known about whether these sex differences contribute to sexually dimorphic regulation of energy balance. Through POMC neuron-specific transcriptome analyses, we identified a number of genes that are expressed in a sexually dimorphic fashion. These include TAp63 (a transcription factor) which is dominant in female POMC neurons, as well as Gabra5 (a GABAA receptor subunit) and SK3 (a small-conductance Ca2+-activated K+ channel) which are both dominant in male POMC neurons. Three mutant mice will be generated to have each of these three genes deleted specifically in POMC neurons, respectively. These mouse strains (both males and females) will be used to determine the physiological roles of these three genes in regulating POMC neuron firing and/or Pomc gene expression, and in maintaining energy homeostasis in different sexes. The functional interactions between these sexually dimorphic genes with the sex hormones will also be examined. Results from these studies will test a hypothesis that multiple sexually dimorphic genes in POMC neurons contribute to the sex differences in POMC neuron functions and body weight balance.

体重平衡中存在性别二态性，但潜在的机制仍然难以捉摸。我们 筛选了一些已知在能量调节中发挥关键作用的神经群体 体内平衡，并发现表达阿片黑皮素原（POMC）的下丘脑神经元表现出性别 两个基本功能的差异：（1）表达 Pomc 基因和（2）激发动作电位。在 特别是，女性 POMC 神经元比男性 POMC 表达更多的 Pomc 基因并且放电更频繁 神经元。这种性别二态性的机制尚不清楚，而且对于这些性别是否存在知之甚少。 差异有助于能量平衡的性别二态性调节。通过 POMC 神经元特异性 通过转录组分析，我们发现了许多以性别二态性方式表达的基因。 其中包括在女性 POMC 神经元中占主导地位的 TAp63（一种转录因子）以及 Gabra5 （GABAA 受体亚基）和 SK3（小电导 Ca2+ 激活的 K+ 通道），两者都是 在雄性 POMC 神经元中占主导地位。将产生三只具有这三个基因的突变小鼠 分别在 POMC 神经元中被特异性删除。这些小鼠品系（雄性和雌性）将 用于确定这三个基因在调节 POMC 神经元放电和/或 Pomc 中的生理作用 基因表达，以及维持不同性别的能量稳态。功能交互 还将检查这些性二态性基因与性激素之间的关系。这些结果 研究将检验一个假设，即 POMC 神经元中的多个性二态性基因有助于 POMC 神经元功能和体重平衡的性别差异。

项目成果

The central melanocortin system and human obesity.

• DOI: 10.1093/jmcb/mjaa048
• 发表时间: 2020-10-01
• 期刊: Journal of molecular cell biology
• 影响因子: 5.5
• 作者: Yang Y;Xu Y
• 通讯作者: Xu Y

Free-floating Immunostaining of Mouse Brains.

• DOI: 10.3791/62876
• 发表时间: 2021-10-07
• 期刊: Journal of visualized experiments : JoVE
• 作者: Tu L;Zhang N;Conde KM;Bean JC;Wang C;Xu Y
• 通讯作者: Xu Y

Eating for hunger or pleasure: a Serotonin Model.

吃饥饿或愉悦的饮食：一种5-羟色胺模型。

• DOI: 10.1093/jmcb/mjab055
• 发表时间: 2021-12-06
• 期刊: Journal of molecular cell biology
• 影响因子: 5.5
• 作者: Yan Z;He Y;Cai X;Shu G;Xu Y
• 通讯作者: Xu Y

SK3 in POMC neurons plays a sexually dimorphic role in energy and glucose homeostasis.

• DOI: 10.1186/s13578-022-00907-2
• 发表时间: 2022-10-09
• 期刊: CELL AND BIOSCIENCE
• 影响因子: 7.5
• 作者: Yu, Meng;Bean, Jonathan C.;Liu, Hailan;He, Yang;Yang, Yongjie;Cai, Xing;Yu, Kaifan;Pei, Zhou;Liu, Hesong;Tu, Longlong;Conde, Kristine M.;Wang, Mengjie;Li, Yongxiang;Yin, Na;Zhang, Nan;Han, Junying;Scarcelli, Nikolas A.;Xu, Pingwen;He, Yanlin;Xu, Yong;Wang, Chunmei
• 通讯作者: Wang, Chunmei