Depression, Adipocytokines and Metabolic Dysregulation in Black and White Women

描述(由申请人提供)：已有文件证明了严重抑郁障碍/抑郁症状与心血管疾病风险(CVD)、发病率和死亡率之间的重要联系。抑郁症与较高的肥胖率、代谢综合征(MetSyn)和糖尿病以及更大的胰岛素抵抗、代谢失调指标和已知的心血管疾病风险因素有关。抑郁症可能通过代谢失调导致心血管疾病风险，但发生这种情况的确切机制尚不清楚。炎症可能起到关键作用。动脉粥样硬化、肥胖、胰岛素抵抗、糖尿病和MetSyn是已知的炎症过程，而抑郁与几种炎症标志物有关。文献中缺乏对抑郁与脂肪细胞因子之间关系的系统研究，脂肪细胞释放的分泌蛋白在炎症过程中发挥关键作用，并被认为在动脉粥样硬化和代谢失调中具有非常重要的意义。对这一应用特别感兴趣的是脂联素和瘦素，脂联素是一种具有胰岛素敏化、抗血栓和抗动脉粥样硬化作用的抗炎脂肪细胞因子，瘦素是一种促炎脂肪细胞因子，密切参与新陈代谢、能量平衡和自主神经系统功能的调节。脂联素和瘦素都独立地与未来心血管事件风险增加和亚临床心血管疾病增加相关。我们将使用来自全国妇女健康研究(SWAN)的现有的、特征良好的非裔美国人和高加索妇女队列来进行我们拟议的研究，其中包括观察队列研究(N=581)和回溯性队列研究(N=266，没有心血管疾病、糖尿病或MetSyn病史)，以检查终生抑郁史和当前抑郁症状与脂联素和瘦素的横向和纵向关系，以及这些脂肪细胞因子在5年内的变化。寻求支持从存储在NIA现有的Swan储存库中的血清样本中检测脂联素和瘦素，并分析和传播我们的发现。通过使用现有的、特征良好的队列和可用的血清样本，我们有一个独特的机会，以极具成本效益的方式测试我们提出的新假设。我们相信，这项研究将为未来R01计划的努力提供重要的数据，这些努力将扩大主要研究人员的研究计划，以更广泛地调查慢性应激、情绪和代谢失调之间的相互关系。这些发现有可能对抑郁症对女性代谢失调和心血管风险的影响产生重要的新见解。公共卫生相关性：这项拟议的研究将在一组中年黑人和白人女性的样本中，研究抑郁症是否与脂肪组织分泌的脂肪细胞因子、脂联素和瘦素有关，这两种生物活性分子在动脉粥样硬化形成和代谢失调中发挥关键作用。这项研究的结果将为抑郁症如何影响女性患糖尿病、代谢综合征、肥胖和心血管疾病的风险提供重要的新信息。

DESCRIPTION (provided by applicant): Important links between major depressive disorder/depressive symptoms and risk for cardiovascular disease (CVD) morbidity and mortality have been documented. Depression is associated with higher rates of obesity, metabolic syndrome (MetSyn) and diabetes and greater insulin resistance, indicators of metabolic dysregulation and known CVD risk factors. Depression likely contributes to CVD risk via metabolic dysregulation but precise mechanisms by which this occurs are unknown. Inflammation may play a key role. Atherogenesis, obesity, insulin resistance, diabetes, and MetSyn are known inflammatory processes, and depression has been linked with several inflammatory markers. Missing from the literature is systematic study of the association between depression and adipocytokines, secretory proteins released from adipocytes that play a critical role in the inflammatory process and are identified as highly significant in atherogenesis and metabolic dysregulation. Of specific interest in this application are adiponectin, an anti-inflammatory adipocytokine with insulin-sensitizing, anti-thrombotic and anti-atherogenic effects, and leptin, a pro-inflammatory adipocytokine intimately involved in regulation of metabolism, energy balance, and autonomic nervous system functioning. Both adiponectin and leptin are independently associated with increased risk of future cardiovascular events and increased subclinical cardiovascular disease. We will use an existing, well-characterized cohort of African-American and Caucasian women from the Study of Women's Health Across the Nation (SWAN) for our proposed research, which includes an observation cohort study (N=581) and a retrospective cohort study (N=266 without a history of CVD, diabetes or MetSyn) to examine both cross-sectional and longitudinal associations of lifetime history of depression and current depressive symptoms with adiponectin and leptin and changes in these adipocytokines over 5 years. Support is sought for assays of adiponectin and leptin from serum specimens stored in the NIA-existing SWAN Repository and for analysis and dissemination of our findings. By using an existing, well-characterized cohort with available serum specimens, we have a unique opportunity to test the novel hypotheses we are proposing in a highly cost-efficient manner. We believe this study will provide important data for future R01 efforts planned that will extend the principal investigators' research program to investigate more broadly the interrelationships of chronic stress, emotions and metabolic dysregulation. Findings have the potential to yield significant new insights regarding the impact of depression on metabolic dysregulation and cardiovascular risk in women. PUBLIC HEALTH RELEVANCE: The proposed study will examine whether depression is associated with the adipocytokines, adiponectin and leptin, bioactive molecules secreted by adipose tissue that play a critical role in atherogenesis and metabolic dysregulation, in a sample of middle-aged black and white women. Results of the study will provide significant new information on how depression affects risk for diabetes, metabolic syndrome, obesity and cardiovascular disease in women.