Metabolic Benefits of Leptin Reduction

瘦素减少的代谢益处

• 批准号: 10436390
• 负责人: JOEL K. ELMQUIST
• 金额: $ 67.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436390
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Adrenergic Receptor; Adult; Affect; Agonist; Animals; Antibodies; Antidiabetic Drugs; Area; Blood Circulation; Body Weight; Body Weight decreased; Brain; Cellular Metabolic Process; Chronic; Closure by clamp; Eating; Energy Metabolism; FGF21 gene; Fatty acid glycerol esters; Food Energy; Food Intake Regulation; GCG gene; Genes; Genetic Transcription; Glucose; Hand; Homeostasis; Hormones; Hypothalamic structure; Individual; Insulin Resistance; Intervention; Laboratories; Lead; Leptin; Leptin deficiency; Leptin resistance; Ligands; Lipids; Lipodystrophy; LoxP-flanked allele; Mediating; Mediator of activation protein; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Metformin; Modeling; Monitor; Nature; Neurons; Obesity; Organ; Peptides; Peripheral; Personal Satisfaction; Pharmacological Treatment; Pharmacology; Physiological; Physiology; Plasma; Play; Population; Positioning Attribute; Preparation; Pro-Opiomelanocortin; Process; Production; Publishing; Recombinants; Records; Regimen; Regulation; Reporter; Role; Series; Signal Transduction; Sympathetic Nervous System; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Transgenic Organisms; Treatment Protocols; Visceral; Work; adipokines; adiponectin; adult obesity; blood glucose regulation; brain tissue; clinical application; diet-induced obesity; experimental study; improved; in vivo; inhibitor; insight; insulin sensitivity; insulin sensitizing drugs; insulin signaling; leptin receptor; metabolic profile; mouse model; overexpression; predictive modeling; response; sexual dimorphism; success; tool

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.

抽象的 瘦素减少的代谢益处 脂肪细胞已成为全身代谢控制的中心舞台。它们调节新陈代谢 多种组织的稳态。脂肪细胞实现这种调节是基于其无与伦比的 储存和中和多余脂质的能力。重要的是，它们通过使用与其他关键器官相互作用 脂肪因子。瘦素和脂联素是被广泛研究的两个最重要的因素。这 编码这些因子的两个基因的 floxed 版本的可用性为我们提供了消除 这两种脂肪因子在成年阶段都有不同程度的发挥。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，全身瘦素水平降低会导致瘦素和胰岛素敏感性增强。相比之下， 通过转基因方式将瘦素水平提高 50%，从而进一步产生瘦素和胰岛素 反抗。在这里，我们的目标是更好地定义这种现象的机制。这包括： 确定哪些抗糖尿病疗法依赖瘦素降低作用来实现其既定作用； b) 阐明降低配体浓度后瘦素致敏的信号传导机制； c) 对不同脂肪垫水平上瘦素产生的控制有深入的了解。我们的 拟议的实验应该为瘦素产生和瘦素作用提供重要的新见解。我们可以 通过我们最近生成的一系列新的、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和 胰岛素敏感性。我们将操纵瘦素受体水平和下游信号传导介质，获得体内 实时瘦素和胰岛素信号传导信息，解决性别二态性反应 瘦素减少并研究脂联素对瘦素表达的影响。 II) 我们将检查是否 抗糖尿病干预措施依赖于减肥前降低瘦素。在这里，我们将重点关注一些 我们将通过转基因方式将瘦素水平“钳制”在基线上的不同已建立的药物 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 这些药剂的作用。 III) 我们将评估中枢瘦素作用是否有所改善 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改善的读数。如果是这样， 哪个神经元亚群参与了这个过程？ IV) 确定关键调解因素 控制瘦素的产生和释放，特别是在内脏脂肪细胞中。我们将检验 3 和 2a 是否 肾上腺素能受体调节成熟脂肪细胞中的瘦素水平。 Scherer/Elmquist 团队及其 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 解决这些问题。重要的是，我们将获得可能对我们的研究产生深远影响的新见解。 对瘦素生理学的具体了解和一般代谢稳态的了解。