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: 9901528
• 负责人: YONG XU
• 金额: $ 35.26万
• 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/9901528
• 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; 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.

性二态性存在于体重平衡中，但潜在的机制仍然难以捉摸。我们 筛选了许多已知在能量调节中起关键作用的神经种群 稳态，发现表达亲欧洲类皮质素（POMC）的下丘脑神经元显示性别 两个基本功能的差异：（1）表达POMC基因和（2）发射动作电位。在 特别是，女性POMC神经元比男性POMC更频繁地表达POMC基因和发射的频率 神经元。这种性二态性的机制尚不清楚，并且对这些性别是否了解 差异有助于对能量平衡的性二态调节。通过POMC神经元特异性 转录组分析，我们确定了许多以性二态性方式表达的基因。 其中包括TAP63（转录因子），该tap63在女性POMC神经元中占主导地位，以及Gabra5 （GABAA受体亚基）和SK3（小传导Ca2+活化的K+通道） 在雄性POMC神经元中占主导地位。将生成三个突变小鼠，以具有这三个基因中的每个基因 分别在POMC神经元中删除。这些小鼠菌株（男性和女性）将是 用于确定这三个基因在调节POMC神经元发射和/或POMC中的生理作用 基因表达，并保持不同性别的能量稳态。功能相互作用 在这些性二态性基因与性激素之间也将进行检查。这些结果 研究将检验一个假设，即POMC神经元中多种性二态基因有助于 POMC神经元功能和体重平衡的性别差异。