Metabolic Benefits of Leptin Reduction

瘦素减少的代谢益处

基本信息

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
项目类别：
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

项目摘要

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。它们调节代谢。多种组织的体内平衡是基于其无与伦比的能力来实现的。重要的是，它们通过使用与其他关键器官相互作用。瘦素和脂联素是已被广泛研究的两个最重要的因素。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会不同程度地降低成年肥胖动物的瘦素水平。我们最近在《细胞代谢》杂志上发表了许多令人惊讶的发现。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。通过转基因方式将瘦素水平提高 50%，从而进一步提高瘦素和胰岛素水平在这里，我们的目标是更好地定义这种现象的机制方面：a）。确定哪些抗糖尿病疗法依赖于瘦素降低作用来实现其既定作用；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。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。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我们将操纵瘦素受体水平和下游信号传导介质，获得体内胰岛素敏感性。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。我们将转基因瘦素水平“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 III) 我们将评估我们是否能改善中枢瘦素的作用。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， IV) 确定哪些神经元亚群参与了这一过程？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 是否存在。肾上腺素能受体调节成熟脂肪细胞中的瘦素水平。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重要的是，我们将获得可能对我们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。