Activation of C/EBP-β by mitohormesis as a therapy for obesity

通过线粒体毒物兴奋作用激活 C/EBP-β 作为肥胖疗法

• 批准号: 10369251
• 负责人: Alessandro Bitto
• 金额: $ 14.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369251
• 关键词: Adipocytes; Adipose tissue; Adult; Aging; Animals; Antioxidants; Architecture; Attenuated; Big Data; Biochemical Pathway; Biological Aging; Biology; Biology of Aging; Body Weight decreased; CCAAT-Enhancer-Binding Proteins; Caloric Restriction; Cardiovascular Diseases; Catabolism; Chronic Disease; DNA polymerase gamma; Data; Data Analyses; Developed Countries; Diabetes Mellitus; Diet; Endocrine; Energy Metabolism; FDA approved; FRAP1 gene; Fatty acid glycerol esters; Gene Expression; Genetic; Geroscience; Glucose tolerance test; Health; Hepatic; Homeostasis; Hyperglycemia; In Vitro; Indirect Calorimetry; Institution; Insulin Resistance; Intervention; Knock-in; Knock-out; Liver; Longevity; MAP Kinase Gene; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Mitochondria; Mitochondrial DNA; Modeling; Morbid Obesity; Mus; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Population; Process; Property; Protein Isoforms; Proteins; Reactive Oxygen Species; Research; Reverse Transcriptase Inhibitors; Risk; Risk Factors; Rodent; Role; Stress; Techniques; Testing; Tissues; Training; Transgenic Model; Transgenic Organisms; Translations; United States; Weight; adefovir dipivoxil; analytical tool; base; biological adaptation to stress; blood glucose regulation; diet-induced obesity; energy balance; experimental study; fatty acid metabolism; fatty acid oxidation; glucose metabolism; in vivo; insight; insulin tolerance; lipid biosynthesis; lipid metabolism; liver metabolism; metabolic phenotype; mitochondrial dysfunction; mouse model; novel; novel strategies; nucleoside analog; nutrient metabolism; obese person; obesity prevention; obesity treatment; obesogenic; p38 Mitogen Activated Protein Kinase; prevent; programs; protein expression; response; side effect; stress activated protein kinase; stressor; tissue culture; transcription factor; virus genetics

Project Summary It is estimated that around 40% of the adult population of the United States is obese and thus at increased risk for several chronic illnesses. Current weight loss strategies for obese people are often ineffective and come with serious neurological side effects. This proposal aims to determine whether new strategies to treat and prevent obesity can be developed from current insights into biological aging. The transcription factor C/EBP-β regulates the expression of genes involved in fat catabolism and fat stores mobilization. Preliminary observations suggest that pro-longevity interventions, such as mTORC1 inhibition, prevent diet-induced obesity in mice and activate C/EBP-β. The nucleoside-analogue reverse-transcriptase inhibitor (NRTI) adefovir dipivoxil (ADV) also prevents diet-induced obesity and activates C/EBP-β, though independently of mTORC1 inhibition. Building on these premises, Aim 1 tests the hypothesis that activation of hepatic C/EBP-β leads to increased energy expenditure and fat catabolism, with net negative effects on weight and fat stores. Using transgenics and pharmacological approaches, we will determine the role of hepatic C/EBP-β in lipid metabolism and homeostasis in the face of obesogenic challenges and morbid obesity. State-of-the-art techniques will be applied to measure the impact of different isoforms of C/EBP-β on energy balance, glucose homeostasis, and endocrine regulation of glucose and lipid metabolism. Aim 2 sets out to determine whether mitohormetic stresses can increase lipid metabolism through activation of C/EBP-β. Using ADV and other mitochondrial stressors, we will measure activation of mitohormetic pathways and their connection with increased hepatic oxidation of fatty acids and energy expenditure. This proposal will be carried out in an institution with strong research programs in both aging and obesity/diabetes biology. The candidate will receive state of the art training in techniques and analytical tools necessary to the completion of both aims, including indirect calorimetry, insulin and glucose tolerance testing, and big data analysis. The candidate will also acquire an in-depth background in energy and nutrient homeostasis. Altogether, the experiments and training proposed will allow the candidate to build an independent and successful research program applying insights from geroscience to understand and investigate nutrient homeostasis, energy balance, and related metabolic disorders.

项目概要 据估计，美国约 40% 的成年人口患有肥胖症，因此肥胖风险增加 用于多种慢性疾病。目前针对肥胖者的减肥策略往往无效并且 具有严重的神经副作用。该提案旨在确定是否有新的策略来治疗和 预防肥胖可以从当前对生物衰老的认识中发展出来。 转录因子 C/EBP-β 调节参与脂肪分解代谢和脂肪储存的基因的表达 动员。初步观察表明，延长寿命的干预措施，例如 mTORC1 抑制， 预防小鼠饮食引起的肥胖并激活 C/EBP-β。核苷类似物逆转录酶 抑制剂 (NRTI) 阿德福韦酯 (ADV) 也可预防饮食引起的肥胖并激活 C/EBP-β 独立于 mTORC1 抑制。 基于这些前提，目标 1 检验了以下假设：肝脏 C/EBP-β 的激活会导致 能量消耗和脂肪分解代谢，对体重和脂肪储存产生净负面影响。使用转基因技术 和药理学方法，我们将确定肝脏 C/EBP-β 在脂质代谢中的作用和 面对致肥挑战和病态肥胖的体内平衡。最先进的技术将 用于测量不同亚型的 C/EBP-β 对能量平衡、葡萄糖稳态和 糖脂代谢的内分泌调节。 目标 2 旨在确定线粒体激素应激是否可以通过激活 C/EBP-β。使用 ADV 和其他线粒体应激源，我们将测量线粒体激素途径的激活 及其与脂肪酸肝脏氧化和能量消耗增加的关系。 该提案将在一个在老龄化和老龄化方面拥有强大研究项目的机构中进行。 肥胖/糖尿病生物学。候选人将接受最先进的技术和分析工具培训 完成这两个目标所必需的，包括间接量热法、胰岛素和葡萄糖耐量测试， 和大数据分析。候选人还将获得能量和营养方面的深入背景 体内平衡。总而言之，所提出的实验和培训将使候选人能够建立一个 独立且成功的研究计划应用老年科学的见解来理解和 研究营养稳态、能量平衡和相关代谢紊乱。