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Metabolic Benefits of Leptin Reduction

瘦素减少的代谢益处

基本信息

批准号：
10621237
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/10621237
关键词：
Acute Address Adipocytes Adipose tissue Adrenergic Receptor Adult Affect Agonist Animals Antibodies Antidiabetic Drugs Area Body Weight Body Weight decreased Brain Cellular Metabolic Process Chronic Circulation Closure by clamp Eating Energy Metabolism FGF21 gene Fatty acid glycerol esters Food Energy Food Intake Regulation GCG gene Genes Genetic Transcription Glucagon Glucose Hand Homeostasis Hypothalamic structure Individual Insulin Resistance Intervention Laboratories Leptin Leptin deficiency Leptin resistance Ligands Lipids Lipodystrophy LoxP-flanked allele Mediating Mediator Metabolic Metabolic Control Metabolic Diseases Metabolism Metformin Modeling Monitor Nature Neurons Obesity Organ Peptides Peripheral Personal Satisfaction Pharmacological Treatment 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 fibroblast growth factor 21 improved in vivo inhibitor insight insulin sensitivity insulin sensitizing drugs insulin signaling leptin receptor metabolic profile mouse model overexpression pharmacologic 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.

摘要