Weight gain, type 2 diabetes, and factors that affect neuroendocrine function

描述(由申请人提供)：肥胖和2型糖尿病(T2D)在非裔美国人(AA)女性中发生的比例不成比例。神经内分泌系统，尤其是下丘脑-垂体-肾上腺(HPA)轴，通过调节能量摄入和消耗，在体重的动态平衡中起着关键作用。围产期事件可能会引起瘦素和胰岛素水平的变化，从而导致下丘脑发育改变，并对体重调节和血糖稳态产生持久影响。慢性应激源会导致HPA轴和交感肾上腺髓质轴的失调，增加肥胖和T2D等代谢性疾病的风险。与美国白人女性相比，AA女性接触到的因素更多，这些因素可能会不利地改变神经内分泌系统的功能。具体地说，再生障碍性贫血妇女不太可能接受母乳喂养，更有可能早产和出生体重低，更有可能经历暴力受害、种族主义、抑郁症和睡眠剥夺。FTO基因是AA和欧洲血统人群中与脂肪质量和肥胖密切相关的基因，在中枢神经系统和下丘脑中高表达，并参与食物摄取调节，因此FTO基因的遗传变异可能是在影响神经内分泌功能的条件下更容易患肥胖症或T2D的个体的特征。我们建议前瞻性地评估上述因素是否与AA女性的体重增加和T2D的发生率相关，以及FTO基因的遗传变异是否改变了这些关联。我们的研究将基于黑人女性健康研究(BWHS)，这是一项正在进行的队列研究，涉及59,000名再生障碍性贫血女性，拥有大量前瞻性收集的数据和存储的DNA样本。自1995年基线以来，BWHS每两年收集一次关于体重的信息，2009年发生了6000多例T2D事件。我们已经发表了体重指数、饮食因素和体力活动与T2D风险的关系，还报告了种族主义和低社会经济地位与BWHS体重增加的积极关联。这项拟议的研究将提供有关可能导致再生障碍性贫血妇女和其他人群中肥胖和T2D流行的因素的新数据。 公共卫生相关性：非裔美国人(AA)妇女受肥胖症和2型糖尿病(T2D)的影响不成比例，并伴随着相关健康问题的沉重负担。这项拟议的研究将提供数据，说明心理社会应激源和其他不利改变神经内分泌系统的因素是否会导致AA女性体重增加和T2D发生率增加。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes (T2D) occur disproportionately among African-American (AA) women. The neuroendocrine system, and in particular the hypothalamic-pituitary-adrenal (HPA) axis, plays a key role in the homeostasis of body weight through regulation of energy intake and expenditure. Perinatal events may cause changes in leptin and insulin levels that lead to altered hypothalamic development and lasting effects on body weight regulation and glucose homeostasis. Chronic stressors can cause deregulation of both the HPA axis and the sympathetic adrenal medullary axis, increasing the risk of developing metabolic diseases such as obesity and T2D. Relative to U.S. white women, AA women have a higher exposure to factors that can unfavorably alter functioning of the neuroendocrine system. Specifically, AA women are less likely to have been breastfed, more likely to have been born preterm and with a low birth weight, and more likely to experience violence victimization, racism, depression, and sleep deprivation. Because the FTO gene, the gene most strongly associated with fat mass and obesity in AA as well as European ancestry populations, is highly expressed in the central nervous system and hypothalamus and is involved in food intake regulation, genetic variants of the FTO gene may characterize individuals who are more susceptible to obesity or T2D under conditions that affect neuroendocrine functioning. We propose to prospectively assess whether the above- mentioned factors are associated with weight gain and incidence of T2D in AA women, and whether genetic variants in the FTO gene modify these associations. Our study will be based on the Black Women's Health Study (BWHS), an ongoing cohort study of 59,000 AA women with a wealth of prospectively collected data and with stored DNA samples. The BWHS has collected information on weight every two years during follow-up since baseline in 1995, and over 6,000 incident cases of T2D have occurred through 2009. We have already published on the relation of body mass index, dietary factors, and physical activity to risk of T2D and have also reported positive associations of racism and low socioeconomic status with weight gain in the BWHS. The proposed study will provide novel data on factors that may be contributing to the epidemic of obesity and T2D in AA women and in other population groups as well. PUBLIC HEALTH RELEVANCE: African American (AA) women are disproportionately affected by obesity and type 2 diabetes (T2D), with a heavy burden of associated health problems. The proposed study will provide data on whether psychosocial stressors and other factors that unfavorably alter the neuroendocrine system, which is involved in regulation of body weight, contribute to increased weight gain and T2D incidence in AA women.