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 减少瘦素的代谢益处 关于系统性代谢控制，脂肪细胞已转移到中心阶段。他们调节代谢 各种组织的稳态。脂肪细胞根据其无与伦比的 能够存储和中和多余的脂质。重要的是，他们通过使用与其他关键器官互动 脂肪因子。瘦素和脂联素是已广泛研究的两个最突出的因素。这 编码这些因素的两个基因的Floxed版本的可用性为我们提供了消除的机会 两种脂肪因子在成人阶段都在不同程度上。降低成年肥胖动物的瘦素水平具有 产生了许多惊喜发现。我们最近在细胞代谢中发表了这些发现，我们 表明全身性瘦素水平的降低会导致瘦素和胰岛素敏感性增强。相比之下， 以转基因方式升高瘦素水平，低至50％，导致进一步的瘦素和胰岛素 反抗。在这里，我们旨在更好地定义这种现象的机械方面。这包括：a） 确定哪些抗糖尿病方案依赖于降瘦素的作用来实现其既定行为； b） 在降低配体浓度后，阐明了瘦素敏感性的信号传导机制； c）在不同脂肪培养基水平上对瘦素产生的控制有一定的了解。我们的 提出的实验应为瘦素产生和瘦素作用提供重大新见解。我们可以 我们最近生成的一系列新的鼠标模型来解决这些问题。 具体而言，我们的目的是：i）确定急性和慢性瘦素降低对周围瘦素和 胰岛素灵敏度。我们将操纵瘦素受体水平和下游信号传导介质，获取体内 实时的瘦素和胰岛素信号传导的信号信息，解决性二态反应 瘦素还原并研究脂联素对瘦素表达的影响。 ii）我们将检查是否 抗糖尿病干预措施取决于减肥之前的瘦素降低。在这里，我们将专注于许多 我们将在基线时通过转基因“夹紧”瘦素水平的不同建立的药物 治疗过程中的水平，或者进一步降低瘦素水平，并用中和抗左侧抗体来增强 这些药物的影响。 iii）我们将评估我们的中央瘦素作用的改善 通过降低瘦素水平建立，需要中央瘦素受体作用以提高读出。如果是这样， 哪些神经元的亚群至关重要地参与此过程？ iv）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是否 肾上腺素受体调节成熟脂肪细胞中的瘦素水平。 Scherer/Elmquist团队，他们 脂肪组织和下丘脑方面的主要专业知识在战略上非常适合 解决这些问题。重要的是，我们将获得新的见解，这可能会对我们的 对瘦素生理学的理解和代谢稳态总体上的理解。