Neural Basis for Leptin Control of Energy Balance

瘦素控制能量平衡的神经基础

• 批准号: 8120686
• 负责人: BRADFORD B LOWELL
• 金额: $ 33.59万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-05 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8120686
• 关键词: Accounting; Address; Alleles; Anatomy; Blood; Body Composition; Body Weight; Body fat; Brain; Cell Nucleus; Chemicals; Corticosterone; Disinhibition; Dorsal; Eating; Electrophysiology (science); Energy Metabolism; Equilibrium; Fatty acid glycerol esters; Fertility; Food Energy; Frequencies; Galanin-Like Peptide; Genes; Glutamates; Homeostasis; Hormones; Hypothalamic structure; Imagery; Interneurons; Knowledge; Lasers; Lateral; Learning; Leptin; Light; Location; Logic; Maps; Mediating; Metabolic; Methods; Middle Hypothalamus; Modeling; Mus; Neurons; Neurotransmitters; Nutritional; Obesity; Phenotype; Physical activity; Play; Regulation; Rest; Role; SF1; Scheme; Signal Transduction; Site; Slice; Structure of nucleus infundibularis hypothalami; Study Section; Subgroup; Synapses; Testing; Thyroid Hormones; Time; Transgenes; Ursidae Family; Work; base; blood glucose regulation; bone mass; energy balance; exhaust; fast-acting neurotransmitter; gamma-Aminobutyric Acid; genetic manipulation; inhibitory neuron; insight; interest; kisspeptin; leptin receptor; mind control; mouse leptin receptor; neural circuit; neurotransmitter release; novel; novel strategies; prevent; programs; public health relevance; receptor; recombinase; relating to nervous system; tool; vector

DESCRIPTION (provided by applicant): Leptin, by acting on leptin receptors (LEPRs) in the brain, exerts marked anti-obesity effects. Since the effects are large and specific, there is great interest in understanding their neural basis (the neurons and neurotransmitters that are involved). To identify the leptin-responsive neurons that initiate leptin's anti-obesity effects, we are genetically deleting LEPRs, in a neuron-specific fashion, and then assessing effects on energy balance. Our earlier studies established that POMC, AgRP and SF1 neurons are involved. However, it is also clear from these studies that a major part of the story is missing - other "first-order", leptin-responding neurons must also be playing an important role. To identify these "other" neurons, we are employing a novel approach - testing leptin-responsive, "first-order" neurons based upon the fast-acting neurotransmitter that they release (i.e. glutamate (excitatory) or GABA (inhibitory)). Towards these ends, we have generated mice that express cre-recombinase in either glutamatergic (VGLUT2-ires-Cre mice) or GABAergic neurons (VGAT-ires-Cre mice). After this, we then created mice that lack LEPRs on glutamatergic or GABAergic neurons. Our preliminary studies indicate that leptin's anti-obesity effects are mediated predominantly by LEPRs on GABAergic neurons. This finding suggests a new logic for piecing together leptin-regulated neural circuits (i.e. a key role for GABAergic inhibitory neurons). Specifically, we propose that leptin action on "local" GABAergic interneurons "indirectly" controls the activity of principle body weight-regulating projection neurons (POMC and possibly AgRP neurons in the arcuate nucleus). A number of approaches are being used to probe this novel hypothesis. These include: 1) Genetic manipulation of LEPRs on GABAergic neurons (and subsets of GABAergic neurons) (in Aims One and Two), 2) Anatomic and electrophysiological analyses to determine the location, identity and function of the relevant leptin-responsive GABAergic neurons (in Aims Two and Three), and 3) Channelrhodopsin-assisted circuit mapping (CRACM) to test the functional connectivity between "upstream" leptin-responsive GABAergic neurons and "downstream" body weight-regulating POMC neurons (in Aim Three). Our hypothesized model is of interest because leptin-responsive GABAergic neurons could be important substrates for nutritional programming and/or metabolic plasticity. PUBLIC HEALTH RELEVANCE: Neurocircuits in the brain control body fat stores. To develop anti-obesity therapies, we must first decipher the "wiring-diagrams" that underpin these circuits. We are using the following approaches to interrogate neural circuits engaged by the anti-obesity hormone, leptin: 1) neuron-specific gene manipulations, 2) optogenetics (light-activated neuronal stimulation) for probing circuit connectivity, and 3) electrical assessments of neuronal function.

描述（由申请人提供）：瘦素通过作用于大脑中的瘦素受体（lepr），具有显著的抗肥胖作用。由于影响是巨大的和特定的，有很大的兴趣了解他们的神经基础（神经元和神经递质参与）。为了确定启动瘦素抗肥胖作用的瘦素反应神经元，我们以神经元特异性的方式从基因上删除lepr，然后评估其对能量平衡的影响。我们早期的研究证实POMC、AgRP和SF1神经元参与其中。然而，从这些研究中也可以清楚地看出，这个故事的一个主要部分被遗漏了——其他“一阶”，瘦素反应神经元也必须发挥重要作用。为了识别这些“其他”神经元，我们采用了一种新的方法-基于它们释放的速效神经递质（即谷氨酸（兴奋性）或GABA（抑制性））测试瘦素反应的“一阶”神经元。为此，我们培育了在谷氨酸能神经元（VGLUT2-ires-Cre小鼠）或gaba能神经元（VGAT-ires-Cre小鼠）中表达cree -重组酶的小鼠。在此之后，我们创造了缺乏谷氨酸能或gaba能神经元lepr的小鼠。我们的初步研究表明，瘦素的抗肥胖作用主要是由gaba能神经元上的lepr介导的。这一发现提出了将瘦素调节的神经回路（即gaba能抑制神经元的关键作用）拼凑在一起的新逻辑。具体来说，我们提出瘦素对“局部”gaba能中间神经元的作用“间接”控制了主要的体重调节投射神经元（弓状核中的POMC和可能的AgRP神经元）的活性。许多方法被用来探索这一新的假设。这些包括:1) gaba能神经元（和gaba能神经元亚群）上lepr的遗传操作（目的一和目的二），2)解剖和电生理分析，以确定相关瘦素反应的gaba能神经元的位置、身份和功能（目的二和目的三），3)通道视紫红质辅助电路映射（CRACM），以测试“上游”瘦素响应的gaba能神经元与“下游”调节体重的POMC神经元之间的功能连接（Aim 3）。我们的假设模型很有趣，因为瘦素反应的gaba能神经元可能是营养规划和/或代谢可塑性的重要基础。