NAD+ and metabolic flexibility

NAD 和代谢灵活性

• 批准号: 10316981
• 负责人: Samuel Klein
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-11 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316981
• 关键词: Acetylation; Adipocytes; Adipose tissue; Adrenergic Agents; Anabolism; Biology; Biopsy Specimen; Blood specimen; Body Weight decreased; Calories; Cell Culture System; Clinical; Coenzymes; Data; Dependovirus; Diet; Energy Metabolism; Enhancers; Enzymes; Exercise; Foundations; Functional disorder; Funding; Genetic; Genetically Engineered Mouse; Grant; High Fat Diet; Human; Impairment; In Vitro; Insulin Resistance; Knockout Mice; Life Style Modification; Link; Liver; Lysine; Mediating; Mediator of activation protein; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Nicotinamide Mononucleotide; Nicotinamide adenine dinucleotide; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Overweight; Oxidation-Reduction; PPARG gene; Persons; Pharmacology; Physiological; Placebos; Prediabetes syndrome; Risk; Rodent; Series; Sirtuins; Skeletal Muscle; Supervision; Supplementation; System; Tamoxifen; Testing; Thermogenesis; Tissues; Visceral; base; caveolin 1; clinically relevant; dietary restriction; exercise training; feeding; flexibility; glucose metabolism; improved; indexing; insight; insulin sensitivity; insulin signaling; mouse model; nicotinamide phosphoribosyltransferase; non-alcoholic fatty liver disease; novel; obesity treatment; overexpression; response; therapeutic target

Obesity is associated with an increased risk of serious metabolic abnormalities, such as type 2 diabetes, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). Data obtained from studies conducted in humans and rodents have suggested that “metabolic inflexibility” is critically involved in the pathophysiology of such metabolic abnormalities. The mechanism(s) responsible for obesity-induced metabolic inflexibility is not clear but could involve altered metabolic activity in white adipose tissue (WAT). In the current funding cycle of this grant, we have focused on studying adipose tissue NAD+ biology and conducted a series of studies that demonstrate the causal relationship between defective WAT NAD+ metabolism and metabolic inflexibility. We found: 1) loss of NAMPT, a key NAD+ biosynthetic enzyme, impairs cellular insulin signaling, mitochondrial function, and adrenergic-stimulated lipolytic activity in WAT; 2) adipocyte-specific Nampt knockout (ANKO) mice have multi-organ (skeletal muscle, liver, WAT) insulin resistance, hypoadiponectinemia, impaired adaptive thermogenesis and whole-body energy metabolism, and impaired fuel selection to hypercaloric and hypocaloric challenges; 3) a novel molecular link between NAD+ metabolism and Caveolin-1 (CAV1), a key regulator of whole-body metabolic flexibility; 4) dietary restriction and exercise, well-known enhancers of metabolic flexibility, stimulate NAMPT-mediated NAD+ biosynthesis in WAT; and 5) consistent with our rodent data, people with obesity have decreases in WAT NAMPT expression and NAD+ concentration. Based on these findings, this renewal application will test the hypotheses that NAMPT-mediated NAD+ biosynthesis regulates CAV1 and mitochondrial function in WAT, key effectors of metabolic flexibility and glucose metabolism, and that defective WAT NAD+ metabolism is a novel mechanism and therapeutic target for obesity-induced metabolic inflexibility. In Aim 1, we propose to generate two novel mouse models, mice overexpressing NAMPT selectively in visceral WAT (using the novel AAV system) and tamoxifen-inducible ANKO (iANKO) mice, and evaluate metabolic responses to high-fat diet feeding and lifestyle modification (dietary restriction, exercise). In Aim 2, we propose to use in vitro systems and explore four mechanisms (lysine acetylation of CAV1, PPARG, sirtuins, and redox metabolism) that link NAD+ metabolism with CAV1 and mitochondrial function. Finally, in Aim 3, we propose to determine the potential clinical relevance of the studies we conducted in the mouse model (Aim 1) and cell culture systems (Aim 2). Specifically, we will evaluate the effects of two potential “NAD+ enhancers”, namely lifestyle modification (low- calorie diet ± supervised exercise training) and nicotinamide mononucleotide (NMN) supplementation (250 mg/day, 8 weeks), on WAT NAD+ metabolism, CAV1, and mitochondrial biology in overweight people. The anticipated results obtained from this proposal will provide novel insight into the importance of adipose tissue NAD+ biology in regulating metabolic flexibility and glucose metabolism.

肥胖与严重代谢异常的风险增加有关，例如2型糖尿病，胰岛素抵抗和非酒精性脂肪肝病（NAFLD）。从人类和啮齿动物进行的研究中获得的数据表明，“代谢不灵活性”与这种代谢异常的病理生理学非常重要。负责肥胖引起的代谢不灵活性的机制尚不清楚，但可能涉及白色脂肪组织（WAT）的代谢活性改变。在该赠款的当前资金周期中，我们专注于研究脂肪组织NAD+生物学，并进行了一系列研究，这些研究证明了有缺陷的WAT NAD+代谢和代谢稳定性之间的因果关系。我们发现：1）NAD+生物合成酶的NAMPT损失会损害WAT中的细胞胰岛素信号传导，线粒体功能和肾上腺素刺激的脂解活性； 2）脂肪细胞特异性的NAMPT敲除（ANKO）小鼠具有多器官（骨骼肌，肝脏，WAT）胰岛素抵抗，低肾上腺胶质性血症，适应性热和全身能量代谢受损，以及对高度和过度挑战的燃料选择受损； 3）NAD+代谢与小窝蛋白-1（CAV1）之间的新分子联系，这是全身代谢柔韧性的关键调节剂； 4）饮食限制和运动，是代谢柔韧性的众所周知的增强子，刺激了WAT中NAMPT介导的NAD+生物合成； 5）与我们的啮齿动物数据一致，肥胖者的表达和NAD+浓度的下降。基于这些发现，这种更新应用将测试NAMPT介导的NAD+生物合成的假设调节Cav1和线粒体功能，代谢灵活性和葡萄糖代谢的关键影响，以及有缺陷的WAT+ NAD+代谢是一种新颖的机制机制和治疗性靶标，对obeSitial-obesility-Meteric-nevelxIndix intelbibity intextimence intextimence-Metebaboric-Indximence-Infelvience。在AIM 1中，我们建议在内脏WAT（使用新型AAV系统）和他莫昔芬诱导的ANKO（Ianko）小鼠中选择性地表达NAMPT的小鼠，并评估对高脂饮食饮食和生活方式改良（饮食限制，运动，运动）的代谢反应。在AIM 2中，我们建议使用体外系统，并探索四种机制（CAV1，PPARG，SIRTUINS和REDOX代谢的赖氨酸乙酰化），将NAD+代谢与CAV1和线粒体功能联系起来。最后，在AIM 3中，我们建议确定我们在小鼠模型（AIM 1）和细胞培养系统（AIM 2）中进行的研究的潜在临床相关性。具体而言，我们将评估两个潜在的“ NAD+增强剂”，即生活方式的修改（低热量饮食±监督运动培训）和烟酰胺单核苷酸（NMN）补充（250 mg/day，8周），对WAT NAD+ NAD+ NAD+代谢性，Cavobolism，cavbolism，cavobolism，cavbolism and cavbolism and cavobolism and cavbolist and Mitochcondrial colyoligy ofertheight perseight ofertheight ofertheight。从该提案中获得的预期结果将提供对脂肪组织NAD+生物学在恢复代谢柔韧性和葡萄糖代谢中的重要性的新见解。