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.

项目概要 肥胖是一个主要的公共卫生问题，影响着大约 35% 的美国成年人，并导致超过 147 美元的损失 每年 10 亿美元的医疗保健支出与多种与年龄相关的疾病（2 型）有关。 糖尿病、心血管疾病、癌症、认知障碍/阿尔茨海默病）以及来自 CDC指出，中年男女和老年女性相比更容易肥胖 对于年轻同事来说，老年人肥胖患病率的增加尤其令人担忧，因为这 到 2050 年，人口普查预计将翻一番。由于肥胖及其相关疾病的患病率不断增加 与年龄相关疾病的关联，确定可以减少肥胖的新干预措施对于 减轻肥胖对我们医疗保健系统的负担并延长美国老年人的健康寿命。 最近，我们的实验室证明了四苯甲酸锰卟啉（MnTBAP）是一种超级氧化物 歧化酶 (SOD) 模拟物，可减少饮食引起的肥胖、胰岛素抵抗和衰老引起的炎症。 和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 我们的初步数据表明，MnTBAP 可能会抑制促 炎症蛋白酶激活受体 2 (PAR2) 信号通路并激活腺苷 单磷酸激活蛋白激酶 (AMPK) 是一种 G 蛋白偶联受体，可促进 炎症，最近被证明在肥胖和胰岛素抵抗的发展中发挥作用。 具体来说，我们证明 MnTBAP 治疗可降低 PAR2 和组织因子 (TF) 的表达， PAR2 信号传导激活剂，并增加组织蛋白酶 G (CTSG) 和蛋白酶 3 的表达 (PRTN3) 是 PAR2 信号传导的两种内源性抑制剂，是细胞能量的主要调节因子。 体内平衡，最近已被证明受到 PAR2 信号传导的抑制，因此，我们的首要目标是 确定 MnTBAP 治疗是否可以预防或减轻与年龄相关的肥胖并改善健康寿命（胰岛素 我们的初步数据还表明，敏感性、血管功能、血压、炎症、血脂）。 MnTBAP 增加 AMPK 活性，我们怀疑这可能与 TF-PAR2 的抑制有关 因此，我们的第二个目标是证明 MnTBAP 治疗可以拮抗 TF-PAR2。 信号通路，一个通过减少 AMPK 与 β-arrestin 2 相互作用来增加 AMPK 活性的过程。 最后，我们该提案的第三个目标是证明完整的 PAR2 信号传导对于 该提案的结果将导致与年龄相关的肥胖、胰岛素抵抗和炎症的发展。 提供证据支持使用 SOD 模拟物和 PAR2 抑制剂作为年龄相关的潜在治疗方法 相关的肥胖、胰岛素抵抗和炎症。