PROJECT 4 - Antagonistic Actions of Melanocortins and Leptin on Reproductive Comp

身体组成、能量平衡和食物摄入的主要调节剂是瘦素，一种脂肪细胞因子[1]。瘦素循环 并通过与瘦素受体的B同种型（LEPR-B）结合而在脑[2]和骨骼肌[3，4]中具有直接作用。 瘦素信号的丢失也会导致下丘脑性腺功能减退和不育。有许多下丘脑 这些细胞核中的每一个都有许多类型的神经元，如它们的定义所示。 神经递质含量[5，6]。有许多证据表明，瘦素反应神经元内 弓状核影响促性腺激素释放。促食欲神经肽NPY [7，8]和AGRP [9]已经被研究。 显示抑制LH释放。弓状核神经元有来自NPY/AGRP神经元的解剖投射 以及从POMC（内啡肽投射）[10]神经元到含有GnRH神经元的内侧视前区[11]。 然而，GnRH神经元的黑皮质素调制的功能影响还没有得到很好的表征。我们提出 初步数据表明，黑皮质素信号对性发育和生殖很重要， 在瘦素信号传导缺陷的背景下的能力。我们建议研究黑素皮质素能神经元 在调节GnRH神经元和生殖功能中的传递。 本提案的目的是研究黑皮质素能传递在介导黑皮质素受体介导的免疫应答中的功能重要性。 瘦素对GnRH神经元功能和生殖能力的影响。我们有四个具体目标， 瘦素调节的神经元细胞类型在生殖系统调节中的作用。 目标1.测定MC 4 R和LEPR联合缺陷小鼠的生殖能力 目的2、确定黑皮质素对GnRH神经元的直接和间接作用 目标3.用瘦素测定女性黑素皮质素能传递增加的生殖能力 受体缺陷 目标4。确定恢复MC 4 R表达对雌性GnRH神经元的影响， LEPR缺陷

A major regulator of body composition, energy balance and food intake is leptin, an adipocytokine [1]. Leptin circulates and has direct actions in the brain [2] and skeletal muscle [3, 4] by binding to the B isoform of leptin receptor (LEPR-B). Loss of leptin signaling also leads to hypothalamic hypogonadism and infertility. There are numerous hypothalamic nuclei that are responsive to leptin and each of these nuclei has numerous types of neurons, as defined by their neurotransmitter content [5, 6]. There are numerous lines of evidence which indicate leptin responsive neurons within the arcuate nucleus affect gonadotropin release. The orexigenic neuropeptides NPY [7, 8] and AGRP [9] have been shown to inhibit LH release. There are anatomical projections of arcuate nucleus neurons from NPY/AGRP neurons and from POMC (endorphin projections) [10] neurons to the medial preoptic area containing GnRH neurons [11]. Nevertheless, the functional impact of melanocortin modulation of GnRH neurons is not well characterized. We present preliminary data to suggest that melanocortin signaling is important to sexual development and reproductive competence within the context of leptin signaling deficiencies. We propose to study the role of melanocortinergic transmission in modulating GnRH neurons and reproductive function. The goals of this proposal are to examine the functional importance of melanocortinergic transmission in mediating the effects of leptin on GnRH neuronal function and reproductive competence. We have four specific aims that address the roles of leptin-regulated neuronal cell types in the regulation of the reproductive system. Aim 1. Determine the reproductive competence of mice with combined MC4R and LEPR deficiencies Aim 2, Determine the direct and indirect effects of melanocortins on GnRH neurons Aim 3. Determine the reproductive competence of increased melanocortinergic transmission in females with leptin receptor deficiency Aim 4. Determine the impact of restoring MC4R expression on GnRH neurons in females with combined MC4R and LEPR deficiencies