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: 10551885
• 负责人: Alessandro Bitto
• 金额: $ 14.68万
• 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/10551885
• 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; Genes; 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; 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; Translations; United States; Viral; Weight; adefovir dipivoxil; analytical tool; biological adaptation to stress; blood glucose regulation; constitutive expression; diet-induced obesity; energy balance; experimental study; factor C; 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; pharmacologic; prevent; programs; protein expression; response; side effect; stress activated protein kinase; stressor; tissue culture; transcription factor

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.

项目摘要 据估计，美国约有40％的成年人口肥胖，因此风险增加 对于几种慢性病。肥胖者的当前减肥策略通常无效，并且来了 具有严重的神经副作用。该建议旨在确定是否要治疗的新策略 可以从当前对生物衰老的见解中发展肥胖。 转录因子C/EBP-β调节涉及脂肪分解代谢和脂肪储存的基因的表达 动员。初步观察结果表明，促态干预措施，例如MTORC1抑制作用， 防止小鼠饮食诱导的肥胖症并激活C/EBP-β。核苷 - 动脉反向转录酶 但是 独立于MTORC1抑制。 在这些前提下，AIM 1检验了以下假设：肝C/EBP-β的激活导致增加 能量消耗和脂肪分解代谢，对体重和脂肪存储有净负面影响。使用转换 和药物方法，我们将确定肝C/EBP-β在脂质代谢和 面对肥胖挑战和病态肥胖症的稳态。最先进的技术将是 用于测量C/EBP-β不同同工型对能量平衡，葡萄糖稳态和 葡萄糖和脂质代谢的内分泌调节。 AIM 2列出以确定有丝旋服应力是否可以通过激活来增加脂质代谢 C/EBP-β。使用ADV和其他线粒体应力源，我们将测量有线摩型途径的激活 以及它们与脂肪酸和能量消耗的肝氧化增加的联系。 该提案将在一个机构中，在衰老和 肥胖/糖尿病生物学。候选人将接受技术和分析工具的最新培训 完成两个目标所必需的，包括间接量热法，胰岛素和葡萄糖耐量测试， 和大数据分析。候选人还将获得能源和养分的深入背景 稳态。总共提出的实验和培训将使候选人能够建立一个 独立和成功的研究计划，采用Geroscience的见解来理解和 研究营养体稳态，能量平衡和相关代谢障碍。