Leptin Receptor and the Obesity/Diabetes Syndrome

描述（由申请人提供）：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。瘦素通过与瘦素受体的B同种型（LEPR-B）结合而在脑和骨骼肌中循环并具有直接作用。虽然瘦素对其他细胞类型（例如免疫细胞和内皮细胞）也有作用，但这些很可能与能量平衡不直接相关。瘦素在下丘脑中的作用已被证明是复杂的。有许多下丘脑核团对瘦素有反应，这些核团中的每一个都有许多类型的神经元，如由它们的神经递质含量所定义的。本研究的目的是探讨POMC/CART神经元、AGRP/NPY神经元和MCH神经元在介导瘦素作用中的功能重要性。我们有三个具体的目标，针对这三个瘦素调节的神经元细胞类型。目标1。确定AGRP缺陷在LEPR-B缺陷女性恢复正常生育力和乳腺发育中的作用。目标2.确定弓状AGRP神经元的AGRP/NPY/GABA传递对肥胖/糖尿病综合征的贡献。目标3.确定瘦素对MCH神经元的直接和间接调节以及这种调节在肥胖/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.