Body fat, dietary restriction, and cancer prevention

描述（由申请人提供）： 热量限制（CR）已被证明可以抑制化学诱导和自发啮齿动物肿瘤模型中的致癌作用。热量限制导致身体脂肪减少，肥胖是众所周知的癌症风险因素。鉴于这种关系（CR导致脂肪减少，CR与抑制致癌作用有关），人们可能会推测体脂与癌症直接相关;然而，体脂在癌症进展和预防中的作用是有争议的。 这项研究将确定身体脂肪量在前列腺癌转基因小鼠模型中对癌症进展的作用。使用固定的食物摄入范例，我们将通过改变对照组和实验动物之间的能量消耗来操纵体脂。将使用最先进的方法（双能X射线吸收测定法和外周定量计算机断层扫描）来无创和纵向测量体脂和体脂分布。能量消耗，因此，身体脂肪量，将被操纵使用环境温度。对照组动物将在35 ℃（其热中性区内的温度）下饲养，实验组动物将维持在24 ℃（必须消耗能量以维持体温的条件）下饲养。增加的体温调节成本，加上固定的能量摄入，将导致实验组相对于对照组动物的体脂量较少。如果CR的癌症预防作用是由于能量摄入的减少，那么对照组和实验组小鼠之间的肿瘤发生率应该没有差异，因为食物摄入量保持不变。相反，如果体内脂肪是CR发挥作用的机制，那么实验动物（饲养在24 ℃下）相对于对照动物（饲养在35 ℃下），由于体内脂肪量较少，前列腺肿瘤的发生率应该会降低。这项研究将为以下假设提供证据：体脂是CR在啮齿动物肿瘤模型中发挥其癌症保护作用的途径。

DESCRIPTION (provided by applicant): Caloric restriction (CR) has been shown to inhibit carcinogenesis in both chemically induced and spontaneous rodent tumor models. Caloric restriction leads to a decrease in body fat, and obesity is a well-known risk factor for cancer. Given this relationship (CR leads to a reduction in fat and CR is associated with an inhibition of carcinogenesis), one might speculate that body fat is directly linked with cancer; however, the role of body fat in cancer progression and prevention is controversial. The proposed study will determine the role of body fat mass on cancer progression in a transgenic mouse mode of prostate cancer. Using a fixed food intake paradigm, we will manipulate body fat by altering energy expenditure between control and experimental animals. State-of-the-art methods (dual-energy X-ray absorptiometry and peripheral quantitative computed tomography) will be used to non-invasively and Iongitudinally measure body fat and body fat distribution. Energy expenditure, and, hence, body fat mass, will be manipulated using ambient temperature. Control animals will be housed at 35xC (a temperature within their thermoneutral zone), and the experimental group will be maintained at 24xC (a condition in which energy must be expended to maintain body temperature). The increased thermoregulatory cost, coupled with a fixed energy intake, will result in a lesser amount of body fat in the experimental group relative to control animals. If the cancer preventative effect of CR is due to a reduction in energy intake, there should be no difference in tumor incidence between control and experimental mice, since food intake is held constant. In contrast, if body fat is the mechanism through which CR works, then the experimental animals (housed at 24oC) should show a decreased incidence of prostate tumors relative to controls (housed at 35oC) due to a lesser amount of body fat. This study will provide evidence for the hypothesis that body fat is the pathway through which CR exerts its cancer protective effects in rodent tumor models.