Human adipose tissue in control of sympathetic tone and metabolic rate

人类脂肪组织控制交感神经张力和代谢率

• 批准号: 10749552
• 负责人: Silvia Corvera
• 金额: $ 72.54万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749552
• 关键词: Acceleration; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Affect; Antidepressive Agents; Basal metabolic rate; Biological Availability; Blood Glucose; Blood Vessels; Body Temperature; Body Weight decreased; Brain; CRISPR/Cas technology; Calories; Cells; Closure by clamp; Communication; Cues; Dependence; Development; Enzymes; Experimental Models; Exposure to; Fasting; Fatty Acids; Fatty acid glycerol esters; Forms Controls; Genes; Grant; Health; Heart; Heart Diseases; Homeostasis; Hormone secretion; Human; Human body; Hybrids; Hyperglycemia; Immunocompromised Host; Implant; Knock-out; Lipolysis; Liver; Measures; Mediating; Mesenchymal Stem Cells; Metabolic; Metabolic Diseases; Metabolism; Methodology; Modeling; Monoamine Oxidase A; Mus; Muscle; NRIP1 gene; Nerve; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obesity; Organ; Organ Temperatures; Physiological; Play; Positioning Attribute; Predisposition; Probability; Proteins; Recycling; Respiration; Role; Signal Transduction; Site; Stimulus; Techniques; Technology; Testing; Therapeutic; Thermogenesis; Tissues; Vascularization; Weight Gain; Work; blood glucose regulation; comparison control; design; disorder risk; fatty liver disease; glucose disposal; glucose metabolism; implantation; improved; in vivo; insulin sensitivity; knock-down; metabolic rate; monoamine; nanoparticle; nerve supply; novel; novel strategies; novel therapeutics; overexpression; pharmacologic; response; stem cells; subcutaneous; virtual

ABSTRACT Sympathetic outflow to adipose tissue regulates whole body energy homeostasis by stimulating lipolysis in white adipocytes and thermogenesis in brown or beige adipocytes. Using a novel approach to study human adipose tissue in mice [1, 2], we have found that, during development, human adipocytes express a high level of monoamine oxidase A (MAOA), a major mechanism for degradation of norepinephrine, and a known target of antidepressant drugs [3]. Notably, expression of Maoa is virtually undetectable in mouse adipocytes, indicating that this control mechanism may have evolved to meet the metabolic features of larger species. We find that human adipocyte MAOA is decreased during beige adipose tissue development, potentially increasing norepinephrine bioavailability, adrenergic tone and thermogenic capacity. Thus, MAOA expression in human adipocytes is a previously underappreciated, key mechanism controlling adipose tissue functions, potentially underlying susceptibility to obesity and metabolic disease. In this proposal, we will further test the hypothesis that adipocyte MAOA controls systemic energy homeostasis through its effects on adipose tissue sympathetic responsiveness. We have developed methodologies to obtain large numbers of human multipotent mesenchymal progenitor cells that can differentiate into multiple adipocyte subtypes, and can generate functional adipose tissue upon implantation in vivo. We have also successfully deleted MAOA from these cells using a novel nanoparticle-based, CRISPR-Cas9 protein delivery technique, resulting in a >90% depletion of MAOA protein while avoiding non-specific effects of expressed Cas9. Leveraging these technologies, we shall: Aim 1. Test the hypothesis that human adipocyte MAOA limits lipolytic and thermogenic responses to norepinephrine. We will measure lipolysis and induction of thermogenesis in control and MAOA-deleted human adipocytes exposed to norepinephrine, as well as steady-state norepinephrine levels and dependency on the monoamine transporter Oct3. Aim 2. We will test the hypothesis that MAOA in human adipocytes regulates the development and responsiveness of thermogenic adipose tissue in vivo. We will measure the rate and extent of vascularization and innervation, and thermogenic responsiveness to environmental stimuli of tissue developed in NSG mice from control or MAOA deleted human adipocytes. Aim 3. We will test the hypothesis that expression of MAOA in adipocytes will determine susceptibility to obesity, systemic insulin sensitivity and systemic glucose homeostasis. We will analyze weight gain, adipocyte size, insulin sensitivity, glucose disposal under hyper insulinemic, hyperglycemic clamps, and basal metabolic rate in mice harboring adipose depots formed from control or MAOA deleted human adipocytes, and in mice overexpressing MaoA in subcutaneous adipose tissue. These aims will provide the basis for further development of tissue specific MAOA-targeting strategies as novel therapeutics for metabolic disease.

抽象的 脂肪组织的交感神经流出通过刺激脂肪分解来调节全身能量稳态 棕色或米色脂肪细胞中的白色脂肪细胞和热发生。使用新颖的方法来研究人 小鼠脂肪组织[1，2]，我们发现在发育过程中，人脂肪细胞表达高水平 单胺氧化酶A（MAOA），一种降解去甲肾上腺素的主要机制和已知的 抗抑郁药的靶标[3]。值得注意的是，在小鼠脂肪细胞中，MAOA的表达实际上是无法检测到的， 表明这种控制机制可能已经发展为满足较大物种的代谢特征。我们 发现在米色脂肪组织发育期间，人脂肪细胞毛发含量减少，可能增加 去甲肾上腺素的生物利用度，肾上腺素能和热能力。因此，毛毛在人类中的表达 脂肪细胞是一种先前低估的控制脂肪组织功能的关键机制， 对肥胖和代谢疾病的潜在敏感性。在此提案中，我们将进一步测试 脂肪细胞MAOA通过其对脂肪组织的影响控制系统的能量稳态的假设 同情的响应能力。我们已经开发了获得大量人类多能的方法 可以分化为多个脂肪细胞亚型的间充质祖细胞，并且可以生成 体内植入后功能性脂肪组织。我们还成功地从这些细胞中删除了MAOA 使用一种新型的基于纳米颗粒的CRISPR-CAS9蛋白输送技术，导致> 90％的耗竭 MAOA蛋白避免了表达Cas9的非特异性作用。利用这些技术，我们 应：目标1。检验人类脂肪细胞MAOA限制了脂解和热反应的假设 去甲肾上腺素。我们将测量对照和MAOA删除的热生成的脂解和诱导 暴露于去甲肾上腺素的人脂肪细胞，以及稳态的去甲肾上腺素水平和对 单胺转运蛋白OCT3。目标2。我们将检验人类脂肪细胞中的MAOA的假设 调节体内热脂肪组织的发育和反应性。我们将衡量 血管形成和神经的速度和程度，以及对环境刺激的热反应能力 由对照或MAOA删除的人脂肪细胞在NSG小鼠中发育的组织。目标3。我们将测试 假设MAOA在脂肪细胞中的表达将决定肥胖，全身胰岛素的敏感性 灵敏度和全身性葡萄糖稳态。我们将分析体重增加，脂肪细胞大小，胰岛素敏感性， 携带的小鼠的高胰岛素，高血糖夹和基底代谢率下的葡萄糖处置 由对照或MAOA删除的人脂肪细胞形成的脂肪仓库，以及在过表达MAOA的小鼠中 皮下脂肪组织。这些目标将为进一步发展组织特定的基础 针对MAOA的策略是代谢疾病的新型治疗方法。