NNAT in metabolic regulation

NNAT 在代谢调节中的作用

基本信息

批准号：
10670959
负责人：
JOHN C YOON
金额：
$ 40.16万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670959
关键词：
ATP Hydrolysis Adipocytes Adipose tissue Adrenergic Agents Adrenergic Receptor Affect Alanine Anti-Obesity Agents Area Back Binding Biological Assay Body Composition Body Weight Brown Fat Ca(2+)-Transporting ATPase Chemicals Child Creatine Data Desire for food Ectopic Expression Endoplasmic Reticulum Energy Metabolism Energy consumption Exhibits Extravasation Fatty acid glycerol esters Fluorescence Resonance Energy Transfer Future Genes Genetic Polymorphism Health Health Care Costs High Fat Diet Human Indirect Calorimetry Knock-out Knockout Mice Link Lipids Lipolysis Marketing Measures Mediating Membrane Proteins Metabolic Modeling Monitor Mus Mutagenesis Obesity Parents Physiological Play Positron-Emission Tomography Process Proteins Pump Reagent Regulation Reporting Resistance Respiration Role Signal Transduction Site Stimulus Temperature Testing Therapeutic Thermogenesis Tissues United States Work blood glucose regulation combat endoplasmic reticulum stress energy balance fluorodeoxyglucose positron emission tomography gain of function improved in vivo inhibitor insight medical complication mouse model novel novel strategies novel therapeutic intervention obesity treatment overexpression pharmacologic phospholamban response sarcolipin small molecule trafficking uncoupling protein 1 uptake warm temperature wasting

项目摘要

PROJECT SUMMARY/ABSTRACT Obesity is associated with serious medical complications and responsible for a rising percentage of health care costs in the United States. While most anti-obesity drugs in the market work by suppressing appetite, increasing energy expenditure by stimulating thermogenesis is an alternative strategy. Humans and mice both possess constitutively active and inducible thermogenic fat, commonly called brown and beige fat. While Uncoupling Protein 1 (UCP1) has long been considered essential for non-shivering thermogenesis in adipose tissues, recent studies have demonstrated UCP1-independent thermogenic mechanisms, and they may be especially important in beige fat. We recently identified the endoplasmic reticulum (ER) membrane protein Nnat as a novel inhibitor of adipocyte thermogenesis and have shown that its effects on thermogenesis are UCP1-independent. We hypothesize that Nnat in adipose tissue plays a key role in controlling thermogenesis and glucose homeostasis. In Aim 1, we will characterize the regulation of systemic energy metabolism by adipose tissue Nnat. In Aim 2, we will investigate the mechanistic basis of Nnat action and will examine its interactions with the ER calcium pump SERCA and other possible ways that Nnat can impact thermogenesis. These studies will produce new insights into the control of adipose tissue thermogenesis and potentially lead to new strategies for anti-obesity therapy.

项目概要/摘要肥胖与严重的医疗并发症有关，导致医疗保健比例不断上升在美国的费用。虽然市场上大多数抗肥胖药物通过抑制食欲起作用，通过刺激产热来增加能量消耗是另一种策略。人和老鼠都具有组成型活性和诱导性产热脂肪，通常称为棕色和米色脂肪。尽管解偶联蛋白 1 (UCP1) 长期以来被认为对于脂肪的非颤抖产热至关重要组织，最近的研究已经证明了 UCP1 独立的生热机制，并且它们可能是在米色脂肪中尤其重要。我们最近鉴定了内质网（ER）膜蛋白 Nnat 作为脂肪细胞生热作用的新型抑制剂，并已表明其对生热作用的影响是独立于 UCP1。我们假设脂肪组织中的 Nnat 在控制生热作用中发挥关键作用和葡萄糖稳态。在目标 1 中，我们将通过以下方式来描述全身能量代谢的调节：脂肪组织 Nnat。在目标 2 中，我们将研究 Nnat 作用的机制基础并检验其与 ER 钙泵 SERCA 的相互作用以及 Nnat 影响生热作用的其他可能方式。这些研究将为脂肪组织生热的控制提供新的见解，并可能导致抗肥胖治疗的新策略。