Attenuation of androgen deprivation therapy-induced metabolic syndrome by diet

通过饮食减轻雄激素剥夺治疗引起的代谢综合征

• 批准号: 8512044
• 负责人: Oleg Varlamov
• 金额: $ 35万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512044
• 关键词: Address; Adipose tissue; Adverse effects; Aerobic Exercise; Age; Androgens; Animals; Area; Biopsy; Body Composition; Body fat; Caloric Restriction; Cancer Etiology; Cancer Patient; Cardiovascular Diseases; Cardiovascular Physiology; Castration; Chemicals; Clinical Trials; Consumption; Crossover Design; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Dyslipidemias; Energy Metabolism; Equilibrium; Exercise; Exposure to; Fat-Restricted Diet; Fatigue; Fatty Acids; Fatty acid glycerol esters; Future; Gene Expression; Goals; Health; Health Benefit; Human; Hyperglycemia; Institutes; Insulin Resistance; Investigation; Life Style; Link; Lipolysis; Longevity; Longitudinal Studies; Macaca mulatta; Malignant Neoplasms; Malignant neoplasm of prostate; Medical History; Metabolic; Metabolic syndrome; Metabolism; Mission; Modeling; Moderate Exercise; Monitor; Monkeys; Muscle; National Cancer Institute; Nursing Research; Nutritional; Obesity; Operative Surgical Procedures; Osteoporosis; Outcome; Patients; Physical environment; Physiological; Preventive Medicine; Public Health; Quality of life; Reducing diet; Reporting; Research; Risk; Second Primary Cancers; Signal Transduction; Skeletal Muscle; Staging; Testing; Testosterone; Time; Tissues; Treatment Efficacy; Visceral; attenuation; blood glucose regulation; cancer diagnosis; cancer therapy; clinical practice; common treatment; cytokine; deprivation; design; diet and exercise; dietary restriction; early onset; energy balance; hormone therapy; improved; insulin sensitivity; insulin signaling; lipid biosynthesis; male; men; middle age; mortality; muscle strength; nonhuman primate; public health relevance; saturated fat; strength training; subcutaneous; uptake

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.

描述（由申请人提供）：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)。后者包括早发性肌肉减少性肥胖和胰岛素抵抗，而较长时间的 ADT 则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的竞争风险和第二大死亡原因。适度的体育锻炼可以逆转肌肉损失，并改善接受 ADT 的患者的总体健康状况。对前列腺癌患者的研究还表明，强烈的生活方式改变，包括低脂饮食 (LFD)，可以减缓前列腺癌的进展，但饮食限制对于减少 ADT 患者多发性硬化症和肥胖的益处尚不清楚。因此，本提案的目标是进一步了解 ADT 相关的多发性硬化症，并确定膳食脂肪对非人类灵长类动物（NHP；恒河猴）多发性硬化症进展和逆转的影响。与人类类似，高脂饮食（HFD）导致恒河猴热量过多会导致肥胖和胰岛素抵抗，而热量限制则可以提高胰岛素敏感性并减少体脂。由于动物可以进行年龄匹配、控制饮食并暴露在相同的物理环境中，因此这种方法消除了由于人类患者在饮食、生活方式和既往病史方面可能存在的混杂差异而导致的变异性。我们假设食用 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多发性硬化症和肥胖，而饮食脂肪限制可以逆转 ADT 诱发的多发性硬化症。为了检验这一假设，我们将确定中年男性的手术去势是否会增加 HFD 引起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，将接受 HFD 的完整动物和去势动物转为低饱和脂肪的热量限制饮食。将以纵向方式监测能量平衡、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WAT的代谢功能。 ADT 的不利影响导致前列腺癌患者死亡率增加，因此对公共健康具有重大影响。在拟议的研究中获得的信息将有助于设计适用于未来人体临床试验和临床实践的新策略。该提案与国家护理研究所和国家癌症研究所的使命直接相关，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，以及开发补充营养方法可以改善癌症的结果。