Metabolic Benefits of Leptin Reduction

摘要 瘦素减少对代谢的益处 脂肪细胞在系统代谢控制方面已经走到了中心舞台。它们调节新陈代谢 各种组织的动态平衡。脂肪细胞在其无与伦比的基础上实现了这种调节 储存和中和多余脂肪的能力。重要的是，它们与其他关键器官通过使用 脂肪因子。瘦素和脂联素是被广泛研究的两个最突出的因素。这个 编码这些因子的两个基因的浮选版本的出现为我们提供了消除 两种脂肪因子在成年阶段都有不同程度的变化。降低成年肥胖动物的瘦素水平 得出了许多令人惊讶的发现。我们最近在《细胞代谢》杂志上发表了这些发现，其中我们 研究表明，全身瘦素水平的降低会导致瘦素和胰岛素敏感性的增强。相比之下， 以转基因方式提高瘦素水平，只有50%，会导致瘦素和胰岛素进一步增加。 抵抗。在这里，我们的目标是更好地定义这一现象的机械方面。这包括：a) 确定哪些抗糖尿病方案依靠降低瘦素的效果来实现其既定的作用；b) 阐明瘦素在降低配体浓度时增敏的信号机制； C)在不同脂肪垫的水平上对瘦素的产生控制有一个坚定的认识。我们的 拟议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。我们可以的 通过我们最近推出的一系列新的、独特的鼠标模型来解决这些问题。 具体地说，我们的目标是：i)确定急性和慢性瘦素减少对外周瘦素和 胰岛素敏感性。我们将操纵瘦素受体水平和下游信号介质，在体内获得 瘦素和胰岛素信号的实时信号信息，解决了性二型反应 瘦素降低，并探讨脂联素对瘦素表达的影响。Ii)我们将研究是否 抗糖尿病干预依赖于在减肥前降低瘦素。在这里，我们将重点关注以下几个方面 不同的已确立的药理作用药物，我们将通过转基因手段将瘦素水平控制在基线水平 治疗期间的瘦素水平，或通过中和抗瘦素抗体进一步降低瘦素水平以增强 这些毒剂的作用。III)我们将评估中枢瘦素作用的改善是否 通过降低瘦素水平建立的，需要中枢瘦素受体的作用来实现更好的读出。如果是的话， 哪个神经元亚群在这一过程中起着至关重要的作用？四)确定关键调解人 控制瘦素的产生和释放，特别是在内脏脂肪细胞中。我们将检查3和2a 肾上腺素能受体调节成熟脂肪细胞中的瘦素水平。Scherer/Elmquist团队，他们的 各自在脂肪组织和下丘脑方面的专业知识，在战略上处于非常有利的地位 回答这些问题。重要的是，我们将获得新的见解，这可能会对我们的 对瘦素生理学和代谢动态平衡的一般理解。

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.