Neurobiology for the sex differences in energy balance

体重平衡中存在性别二态性，但其潜在机制仍不清楚。我们 筛选了一些已知在能量调节中起关键作用的神经群， 稳态，并发现下丘脑神经元表达前阿黑皮素（POMC）显示性别 两种基本功能的差异：（1）表达Pomc基因和（2）激发动作电位。在 特别是，女性POMC神经元表达更多的Pomc基因，比男性POMC神经元更频繁地放电 神经元这种两性异形的机制尚不清楚，也不知道这些性别是否 差异导致能量平衡的两性异形调节。通过POMC神经元特异性 通过转录组分析，我们鉴定了许多以性二态方式表达的基因。 这些包括在雌性POMC神经元中占优势的TAp 63（转录因子），以及Gabra 5 （GABAA受体亚基）和SK 3（小电导Ca 2+激活的K+通道），两者都是 在雄性POMC神经元中占主导地位。三个突变小鼠将产生这三个基因的每一个 在POMC神经元中特异性缺失。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，并在维持能量稳态在不同性别。功能性相互作用 还将检查这些性二态基因与性激素之间的关系。从这些 研究将验证一个假设，即POMC神经元中的多个性二态基因有助于 POMC神经元功能和体重平衡的性别差异。

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.