Age-Related Obesity and Healthspan: Identifying Interventions and Mechanisms

项目摘要 肥胖是一个主要的公共卫生问题，影响了大约35%的美国成年人，导致超过147美元的收入。 每年医疗保健支出10亿美元。肥胖与几种年龄相关疾病（2型 糖尿病、心血管疾病、癌症、认知障碍/阿尔茨海默氏症）以及来自 疾病预防控制中心指出，中年男女和老年妇女更容易患肥胖症， 年轻的同行。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。由于肥胖症的日益流行及其 与年龄相关的疾病，确定新的干预措施，可以减少肥胖是必不可少的， 减轻肥胖对我们医疗保健系统的负担，改善美国老年人的健康寿命。 最近，我们实验室发现，超氧化物四苯甲酸锰卟啉（MnTBAP） 歧化酶（SOD）模拟物，减少饮食诱导的肥胖、胰岛素抵抗和炎症。因为衰老 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- 相关的肥胖症和相关疾病。我们的初步数据表明，MnTBAP可能会抑制亲- 炎症蛋白酶激活受体2（PAR 2）信号通路，并激活腺苷 单磷酸活化蛋白激酶（AMPK）。PAR 2是一种G蛋白偶联受体， 炎症，最近已被证明在肥胖和胰岛素抵抗的发展中起作用。 具体来说，我们证明MnTBAP处理降低了PAR 2和组织因子（TF）的表达， PAR 2信号传导的活化剂，以及增加组织蛋白酶G（CTSG）和蛋白酶3的表达 （PRTN 3），PAR 2信号传导的两种内源性抑制剂。AMPK是细胞能量的主要调节因子 体内平衡，并且最近已显示被PAR 2信号传导抑制。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改善健康状况（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增加AMPK活性，我们怀疑这可能与TF-PAR 2的抑制有关 发信号。因此，我们的第二个目的是证明MnTBAP处理拮抗TF-PAR 2 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，我们的第三个目的是证明完整的PAR 2信号传导是需要的， 与年龄相关的肥胖、胰岛素抵抗和炎症的发展。该提案的结果将 提供支持使用SOD模拟物和PAR 2抑制剂作为年龄- 相关的肥胖、胰岛素抵抗和炎症。

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.