Metabolic Benefits of Leptin Reduction

摘要 减少瘦素的代谢益处 脂肪细胞已经成为系统代谢控制的中心。它们调节新陈代谢 各种组织的内稳态。脂肪细胞实现这种调节的基础上，其无与伦比的 储存和中和多余脂质的能力。重要的是，它们通过使用 脂肪因子瘦素和脂联素是两个最突出的因素，已被广泛研究。的 编码这些因子的两种基因的floxed版本的可用性为我们提供了消除 这两种脂肪因子在成人阶段都有不同程度的表达。降低成年肥胖动物的瘦素水平， 得出了一些惊人的发现我们最近在Cell Metabolism上发表了这些发现， 表明全身瘦素水平的降低导致瘦素和胰岛素敏感性的增强。与此相反， 以转基因方式提高瘦素水平，低至50%，导致进一步的瘦素和胰岛素 阻力在这里，我们的目标是更好地定义这一现象的机制方面。这包括：a） 确定哪些抗糖尿病方案依赖于瘦素降低作用来实现其既定作用; B） 阐明降低配体浓度时瘦素敏化的信号传导机制; c）在不同脂肪垫水平上获得对瘦素产生的控制的坚定理解。我们 所提出的实验应该为瘦素的产生和瘦素的作用提供重要的新见解。我们可以 用我们最近制作的一系列新的独特的小鼠模型来解决这些问题。 具体来说，我们的目标是：I）确定急性和慢性瘦素减少对外周瘦素的影响， 胰岛素敏感性我们将操纵瘦素受体水平和下游信号介质，获得体内 真实的时间的瘦素和胰岛素信号传导的信号传导信息，解决了对 研究脂联素对瘦素表达的影响。（二）我们将研究 抗糖尿病干预依赖于在体重减轻之前降低瘦素。在这里，我们将重点介绍一些 不同的已建立的药物，我们将“钳”瘦素水平在基线转基因 治疗期间的瘦素水平，或用中和性抗瘦素抗体进一步降低瘦素水平以增强 这些代理商的影响。III）我们将评估我们所观察到的中枢瘦素作用的改善是否 通过降低瘦素水平而建立，需要中枢瘦素受体作用以实现改善的读出。如果是这样， 哪个神经元亚群在这个过程中起着关键作用？IV）确定关键的调解人， 控制瘦素的产生和释放，特别是在内脏脂肪细胞中。我们将研究是否有103和102 a 肾上腺素能受体调节成熟脂肪细胞中的瘦素水平。谢勒/埃尔姆奎斯特团队， 在脂肪组织和下丘脑各自的专业知识，是战略上非常好的定位， 回答这些问题。重要的是，我们将获得新的见解，这可能对我们的 具体了解瘦素生理学和一般代谢稳态。

Abstract Metabolic Benefits of Leptin Reduction Adipocytes have moved to center stage with respect to systemic metabolic control. They regulate metabolic homeostasis for a variety of tissues. Adipocytes achieve this regulation on the basis of their unsurpassed ability to store and neutralize excess lipids. Importantly, they interact with other critical organs through the use of adipokines. Leptin and adiponectin are the two most prominent factors that have been widely studied. The availability of floxed versions of both genes encoding these factors has offered us the opportunity to eliminate both adipokines in the adult stage to varying degrees. Reducing leptin levels in adult obese animals has yielded a number of surprising findings. We recently published these findings in Cell Metabolism, in which we showed that a reduction in systemic leptin levels results in enhanced leptin and insulin sensitivity. In contrast, elevating leptin levels in a transgenic manner, by as little as 50%, results in further leptin and insulin resistance. Here, we aim to better define the mechanistic aspects of this phenomenon. This includes: a) determining which anti-diabetic regimens rely on leptin-lowering effects to achieve their established actions; b) elucidating the signaling mechanisms underlying leptin sensitization upon reducing the ligand concentrations; c) gaining a firm understanding on the control of leptin production at the level of different fat-pads. Our proposed experiments should provide significant new insights into leptin production and leptin action. We can address these questions with a series of new and unique mouse models that we recently generated. Specifically, we aim to: I) Determine the effects of acute and chronic leptin reduction on peripheral leptin and insulin sensitivity. We will manipulate leptin receptor levels and downstream signaling mediators, obtain in vivo signaling information for both leptin and insulin signaling in real time, address sexually dimorphic responses to leptin reduction and investigate the impact of adiponectin on leptin expression. II) We will examine whether anti-diabetic interventions rely on leptin lowering prior to weight loss. Here, we will focus on a number of different established pharmacological agents for which we will “clamp” leptin levels transgenically at baseline levels during treatment, or further reduce leptin levels with neutralizing anti-leptin antibodies to enhance the effects of these agents. III) We will assess whether the improvements in central leptin action that we established by lowering leptin levels, require central leptin receptor action to achieve improved read-outs. If so, which subpopulation of neurons is critically involved in this process? IV) Determine the critical mediators that govern leptin production and release, particularly in the visceral adipocyte. We will examine whether 3 and 2a adrenergic receptors regulate leptin levels in the mature adipocyte. The Scherer/Elmquist team, with their respective expertise in adipose tissue and the hypothalamus, is strategically extremely well positioned to address these questions. Importantly, we will gain new insights that may have a profound effect on our understanding of leptin physiology specifically and metabolic homeostasis in general.