Leptin Receptor and the Obesity/Diabetes Syndrome

描述（由申请人提供）：身体成分、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 B 亚型 (LEPR-B) 结合而在大脑和骨骼肌中循环并直接发挥作用。虽然瘦素对其他细胞类型（例如免疫细胞和内皮细胞）有作用，但这些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。有许多下丘脑核对瘦素有反应，并且每个核都有多种类型的神经元，根据其神经递质含量来定义。该提案的目标是检查 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。我们针对这三种瘦素调节的神经元细胞类型制定了三个具体目标。目标 1. 确定 AGRP 缺陷在 LEPR-B 缺陷女性恢复正常生育能力和乳腺发育中的作用。目标 2. 确定弓形 AGRP 神经元的 AGRP/NPY/GABA 传递对肥胖/糖尿病综合征的影响。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对肥胖/糖尿病综合征的意义。

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.