Attenuation of androgen deprivation therapy-induced metabolic syndrome by diet

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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.