Attenuation of androgen deprivation therapy-induced metabolic syndrome by diet

描述(申请人提供)：早期前列腺癌患者最常见的治疗方法是雄激素剥夺疗法(ADT)。ADT有多种副作用，包括生活质量下降、瘦体重和肌肉力量下降、骨质疏松症和代谢综合征(MS)。后者包括早期发生的骨质疏松性肥胖和胰岛素抵抗，而ADT持续时间较长与糖尿病和血脂异常有关。心血管疾病已被认为是前列腺癌男性死亡的竞争风险和第二大原因。适度的体育锻炼可以逆转ADT患者的肌肉损失，改善患者的整体健康状况。对前列腺癌患者的研究还表明，密集改变生活方式，包括低脂肪饮食(LFD)，可以减缓前列腺癌的进展，但限制饮食对减少多发性硬化症和ADT患者肥胖的好处尚不清楚。因此，本提案的目的是加深我们对ADT相关多发性硬化的理解，并建立饮食脂肪对非人类灵长类动物(NHP；恒河猴)多发性硬化进展和逆转的影响。与人类相似，高脂饮食(HFD)给恒河猴带来的卡路里过量会导致肥胖和胰岛素抵抗，而限制卡路里则会改善胰岛素敏感性，减少体脂。由于动物可以年龄匹配，保持受控饮食，并暴露在相同的物理环境中，这种方法消除了由于饮食、生活方式和人类患者既往病史可能存在的混淆差异而产生的变异性。我们假设摄入HFD会夸大ADT对白色脂肪组织(WAT)功能的负面影响，导致前列腺癌患者发生MS和肥胖，并且限制饮食脂肪可以逆转ADT诱导的MS。为了检验这一假说，我们将确定对中年男性进行手术去势是否会增加HFD诱导的胰岛素抵抗和肥胖的风险和程度。为了确定饮食限制是否可以消除或减少ADT的代谢副作用，对HFD的完整和去势动物将切换到低饱和脂肪的卡路里限制饮食。将纵向监测能量平衡、细胞因子水平、胰岛素敏感性和身体成分的变化，并通过纵向活检检查皮下和内脏水的代谢功能。ADT的不良反应导致前列腺癌患者的额外死亡率，因此具有重大的公共卫生影响。拟议研究中获得的信息将有助于设计适用于未来人类临床试验和临床实践的新策略。这项建议直接关系到国家护理研究所的使命和国家癌症研究所的使命，即促进与预防医学和传统癌症治疗副作用管理相关的研究，以及开发可改善癌症结果的补充营养方法。

DESCRIPTION (provided by applicant): The most common treatment for patients with early-stage prostate cancer is androgen-deprivation therapy (ADT). ADT has multiple adverse effects, including decreased quality of life, decreased lean mass and muscle strength, osteoporosis, and metabolic syndrome (MS). The later includes the early onset of sarcopenic obesity and insulin resistance, while longer duration of ADT is associated with diabetes, and dyslipidemia. Cardiovascular disease has been recognized as the competing risk and the second cause of mortality in men with prostate cancer. Moderate physical exercise can reverse muscle loss, and improve general health of patients undergoing ADT. Studies in prostate cancer patients also demonstrated that intensive lifestyle changes, including a low-fat diet (LFD), can slow the progression of prostate cancer, but the benefits of a diet restriction for reducing MS and obesity in ADT patients are unknown. Thus, the goal of the present proposal is to further our understanding of the ADT-related MS and establish the effects of dietary fats on the progression and reversal of MS in non-human primates (NHP; rhesus macaques). Similar to humans, caloric excess in rhesus monkeys brought about by a high fat diet (HFD) leads to obesity and insulin resistance, while caloric restriction results in improved insulin sensitivity, and decreased body fat. Because animals can be age- matched, kept on controlled diets, and exposed to the same physical environment, this approach eliminates the variability due to possible confounding differences in diet, lifestyle, and previous medical history seen in human patients. We hypothesize that consumption of a HFD exaggerates the negative effects of ADT on white adipose tissue (WAT) function, leading to the development of MS and obesity in prostate cancer patients and that dietary fat restriction can reverse ADT-induced MS. To test this hypothesis, we will determine whether surgical castration of middle-aged males increases the risk and the magnitude of HFD- induced insulin resistance and obesity. To determine if dietary restriction can eliminate or reduce the metabolic side effects of ADT, intact and castrated animals on a HFD will be switched to a calorie-restricted diet low in saturated fats. Changes in energy balance, cytokine levels, insulin sensitivity, and body composition will be monitored in a longitudinal fashion, and the metabolic function of subcutaneous and visceral WAT will be examined via longitudinal biopsies. The adverse effects of ADT result in additional mortality in prostate cancer patients and, thus, have significant public health implications. The information obtained in the proposed study will help design new strategies applicable to future human clinical trials and clinical practice. This proposal is directly related to the mission of the Natinal Institute of Nursing Research and to the mission of the National Cancer Institute to promote research related to preventive medicine and the management of side effects of conventional cancer treatment, as well as to develop complementary nutritional approaches that can improve cancer outcomes.