Age-Related Obesity and Healthspan: Identifying Interventions and Mechanisms

与年龄相关的肥胖和健康寿命：确定干预措施和机制

• 批准号: 9171143
• 负责人: THOMAS H REYNOLDS
• 金额: $ 39.32万
• 依托单位: SKIDMORE COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9171143
• 关键词: Ablation; Academic Research Enhancement Awards; Acetyl-CoA Carboxylase; Adenosine Monophosphate; Adipose tissue; Adult; Affect; Aging; Alzheimer' s Disease; American; Antioxidants; Attenuated; Benzoic Acids; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cathepsin G; Censuses; Centers for Disease Control and Prevention (U.S.); Coupled; Data; Development; Disease; Elderly; Female; G-Protein-Coupled Receptors; Genes; Goals; Health Care Costs; Health Expenditures; Healthcare Systems; Homeostasis; Impaired cognition; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intervention; Knockout Mice; Laboratories; Malignant Neoplasms; Manganese; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity associated disease; Osteoporosis; Oxidative Stress; Oxides; PAR-2 Receptor; Pathway interactions; Phosphorylation; Plasma; Play; Population; Porphyrins; Prevalence; Process; Protein Kinase; Protein Kinase Interaction; Proteinase 3; Public Health; Reducing diet; Role; Signal Pathway; Signal Transduction; Site; Thromboplastin; Tissues; Triglycerides; United States; Woman; Work; age related; aged; arrestin 2; beta-arrestin; blood lipid; catalase; effective intervention; effective therapy; improved; inhibitor/antagonist; insulin sensitivity; male; men; middle age; mimetics; novel; older women; porphyrin a; prevent; sarcopenia; vascular inflammation

PROJECT SUMMARY Obesity is a major public health problem that affects approximately 35% of US adults and results in over $147 billion in annual health care expenditures. Obesity is associated with several age-related diseases (type 2 diabetes, cardiovascular disease, cancer, cognitive impairment/Alzheimer's) and the most recent data from the CDC indicates that middle-aged men and women and older women are more susceptible to obesity compared to their younger counterparts. Increased prevalence of obesity in older adults is particularly alarming since this population's census is expected to double by 2050. Because of the increasing prevalence of obesity and its association with age-related diseases, identifying novel interventions that can reduce adiposity is essential to decrease the burden of obesity on our health care system and improve the healthspan of older Americans. Recently, our lab has shown that manganese tetrakis benzoic acid porphyrin (MnTBAP), a super oxide dismutase (SOD) mimetic, reduces diet-induced obesity, insulin resistance, and inflammation. Because aging and obesity are tightly coupled to increases in oxidative stress and inflammation, MnTBAP may reduce age- related obesity and associated diseases. Our preliminary data shows that MnTBAP may inhibit the pro- inflammatory protease activated receptor 2 (PAR2) signaling pathway and activate the adenosine monophosphate activated protein kinase (AMPK). PAR2 is a G protein coupled receptor that promotes inflammation and has recently been shown to play a role in the development of obesity and insulin resistance. Specifically, we demonstrate that MnTBAP treatment reduces the expression of PAR2 and tissue factor (TF), an activator of PAR2 signaling, as well as increase the expression of cathepsin G (CTSG) and proteinase 3 (PRTN3), two endogenous inhibitors of PAR2 signaling. AMPK is a master regulatory of cellular energy homeostasis and has recently been shown to be inhibited by PAR2 signaling. Therefore, our first aim is to determine if MnTBAP treatment can prevent or attenuate age-related obesity and improve healthspan (insulin sensitivity, vascular function, blood pressure, inflammation, blood lipids). Our preliminary data also suggests that MnTBAP increases AMPK activity and we suspect this may be related to an inhibition of TF-PAR2 signaling. Therefore, our second aim is to demonstrate that MnTBAP treatment antagonizes the TF-PAR2 signaling pathway, a process that increases AMPK activity by decreasing AMPK's interaction with β-arrestin 2. Finally, our third aim of this proposal is to demonstrate that intact PAR2 signaling is required for the development of age-related obesity, insulin resistance, and inflammation. Results from this proposal will provide evidence supporting the use of SOD mimetics and PAR2 inhibitors as potential treatments for age- related obesity, insulin resistance, and inflammation.

项目总结 肥胖是一个主要的公共健康问题，影响着大约35%的美国成年人，导致超过147美元的收入 每年的医疗保健支出为10亿美元。肥胖与几种年龄相关的疾病(2型)有关 糖尿病、心血管疾病、癌症、认知障碍/阿尔茨海默氏症)和来自 美国疾病控制与预防中心指出，与中年男性、女性和老年女性相比，中年男性更容易患肥胖症 给年轻的同龄人。老年人肥胖率的上升尤其令人担忧，因为 预计到2050年，人口普查将翻一番。因为肥胖症的流行程度越来越高，而且 与年龄相关的疾病有关，确定可以减少肥胖的新干预措施对于 减轻肥胖给我们的医疗保健系统带来的负担，提高美国老年人的健康寿命。 最近，我们的实验室发现了一种超氧化物四苯基锰卟啉(MnTBAP) 超氧化物歧化酶(SOD)类似物，可减少饮食引起的肥胖、胰岛素抵抗和炎症。因为年龄的增长 肥胖与氧化应激和炎症的增加密切相关，MnTBAP可能会降低年龄- 相关的肥胖和相关疾病。我们的初步数据显示，MnTBAP可能抑制PRO-1。 炎性蛋白水解酶激活受体2(PAR2)信号通路与腺苷激活 一磷酸活化蛋白激酶(AMPK)。PAR2是一种G蛋白偶联受体，促进 炎症，最近被证明在肥胖和胰岛素抵抗的发展中发挥了作用。 具体地说，我们证明了MnTBAP治疗降低了PAR2和组织因子(TF)的表达， PAR2信号的激活剂，以及增加组织蛋白酶G(CTSG)和蛋白酶3的表达 (PRTN3)是PAR2信号转导的两种内源性抑制物。AMPK是细胞能量的主要调节因子 动态平衡，最近被证明被PAR2信号抑制。因此，我们的首要目标是 确定MnTBAP治疗是否可以预防或减轻年龄相关性肥胖并提高健康寿命(胰岛素 敏感性、血管功能、血压、炎症、血脂)。我们的初步数据还表明 MnTBAP增强AMPK活性，我们怀疑这可能与抑制Tf-PAR2有关 发信号。因此，我们的第二个目标是证明MnTBAP治疗拮抗Tf-PAR2 信号通路，通过减少AMPK与β-arrestin 2的相互作用来增加AMPK活性的过程。 最后，我们这个提案的第三个目标是证明完整的PAR2信令是 与年龄相关的肥胖、胰岛素抵抗和炎症的发展。这项提案的结果将是 提供证据支持使用超氧化物歧化酶模拟物和PAR2抑制剂作为治疗年龄的潜在方法- 与肥胖、胰岛素抵抗和炎症相关。