Leptin Receptor and the Obesity/Diabetes Syndrome

描述(申请人提供)：瘦素是一种脂肪细胞因子，是身体成分、能量平衡和食物摄入量的主要调节器。瘦素通过与B亚型瘦素受体(LEPR-B)结合，在脑和骨骼肌中循环并发挥直接作用。虽然瘦素对其他类型的细胞也有作用，如对免疫细胞和内皮细胞，但这些作用很可能与能量平衡没有直接关系。瘦素在下丘脑中的作用已被证明是复杂的。下丘脑有许多对瘦素有反应的核团，每个核团都有许多类型的神经元，根据它们的神经递质含量来定义。该方案的目的是研究POMC/CART神经元、AGRP/NPY神经元和MCH神经元在介导瘦素效应中的功能重要性。我们有三个特定的目标，针对这三种瘦素调节的神经细胞类型。目的1.确定AGRP缺乏对LEPR-B缺陷女性恢复正常生育和乳腺发育的作用。目的2.确定弓状AGRP神经元的AGRP/NPY/GABA传递在肥胖/糖尿病综合征中的作用。目的3.确定瘦素对MCH神经元的直接和间接调节及其在肥胖/糖尿病综合征中的意义。

DESCRIPTION (provided by applicant): A major regulator of body composition, energy balance and food intake is leptin, an adipocytokine. Leptin circulates and has direct actions in the brain and skeletal muscle by binding to the B isoform of leptin receptor (LEPR-B). While there are actions of leptin on other cell types, such as on immune cells and endothelial cells, these are most likely not directly relevant to energy balance. Leptin action in the hypothalamus has proven to be complex. 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. The goals of this proposal are to examine the functional importance of POMC/CART neurons, AGRP/NPY neurons and MCH neurons in mediating the effects of leptin. We have three specific aims that are targeted to these three leptin-regulated neuronal cell types. Aim 1. Determine the role of AGRP deficiency in restoring normal fertility and mammary gland development to LEPR-B deficient females. Aim 2. Determine the contribution of AGRP/NPY/GABA transmission from arcuate AGRP neurons to the obesity/diabetes syndrome. Aim 3. Determine the direct and indirect regulation of MCH neurons by leptin and the significance of this regulation to the obesity/diabetes syndrome.