ACUTE AND CHRONIC CALORIE RESTRICTION AND THE METABOLIC SYNDROME

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 胰岛素抵抗是代谢综合征的一个潜在特征，并与内皮功能障碍和冠心病有关。 体重减轻改善肥胖受试者的胰岛素敏感性、内皮功能和代谢综合征的所有特征。 此外，短期的热量限制，没有显着的体重减轻，提高胰岛素的作用。 然而，尚不清楚急性热量限制引起胰岛素作用改善的机制，以及特定常量营养素或总能量摄入的减少是否是有益效果的原因。 此外，目前尚不清楚短期热量限制是否会改善内皮功能。 因此，本项目的主要目的是评估急性和慢性热量限制对代谢综合征患者血管疾病发病机制中的两个关键因素胰岛素敏感性和炎症的影响的潜在机制。 我们假设短期的热量限制通过改变脂肪酸代谢和炎症来影响胰岛素的作用。 更具体地说，我们假设热量限制与足够的碳水化合物摄入量（>=120 g/d）改善胰岛素作用，炎症和内皮功能（血管疾病的标志物），而急性热量限制与低碳水化合物摄入量（<=40 g/d）将损害这些参数，因为增加脂肪酸通量。 我们还提出，适度的减肥，无论是由低脂或低碳水化合物饮食引起的，由于基因表达的长期修饰，对胰岛素作用、炎症和内皮功能的有益影响将大于短期热量限制。 更好地了解急性和慢性能量限制对血管疾病代谢危险因素影响的机制，可能会为患有代谢综合征的肥胖患者提供更有效的治疗策略。 将40名（BMI 30-45 kg/ms）受试者随机接受具有足够（>=120 g/d）或低（<=40 g/d）碳水化合物含量的低热量饮食。 饮食将提供50%的热量不足，预先和姿势测量身体组成，两阶段正常血糖高胰岛素钳夹与稳定同位素标记的示踪剂输注，磁共振波谱（MRS）和肌肉活检。 在两天的急性热量限制之后，受试者将继续相同的50% kcal限制饮食，直到他们失去其初始体重的5%。 一旦受试者体重减轻5%，将调整其总卡路里摄入量，以维持恒定的体重并防止进一步体重减轻。 在受试者保持5%的体重减轻约3周后，将重复进行身体成分分析、基线血液检查和同位素输注研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance is an underlying eature of the metabolic syndroe, and is associated with endothelial dysfunction and coronary heart disease. Weight loss improves insulin sensitivity, endothelial function, and all features of the metabolic syndrome in obese subjects. In addition, short-term calorie restriction, without significant weight loss, improves insulin action. However, the mechanism(s) responsible for the improvement in insulin action induced by acute calorie restriction, and whether a decrease in a specific macronutrient or total energy intake is responsible for the beneficial effects, are not known. Moreover, it is not known whether short-term calorie restriction improves endothelial function. Therfore, the primary goal of this project is to evaluate the potential mechanisms responsible for the effect of acute and chronic calorie restriction on two key factors involved in the pathogenesis of vascular disease, insulin sensitivity and inflammation, n subjects with the metabolic syndrome. We hypothesize that short-term caloric restriction affects insulin action by altering fatty acid metabolism and inflammation. More specifically, we hypothesize that calorie restriction with adequate carbohydrate intake (>=120 g/d) improves insulin action, inflammation, and endothelial function (a marker of vascular disease) while acute calorie restriction with low carbohydrate intake (<=40 g/d) will impair these parameters because of increased fatty acid flux. We also propose that moderate weight loss, whether induced by low-fat or low carbohydrate diets, will have greater beneficial effects on insulin action, inflammation and endothelial function that short-term caloric restriction because of long-term modification of gene expression. A better understanding of the mechanisms responsible for the effect of acute and chronic energy restriction on metabolic risk factors for vascular disease could lead to more effective treatment strategies for obese patients who have the metabolic syndrome. Forty (BMI 30-45 kg/ms) subjects will be randomize to receive a hypocaloric diet with either adequate (>=120 g/d) or low (<=40 g/d) carbohydrate content. The diet will provide a 50% calorie deficit with pre and pose measures of body composition, two-stage euglycemic hyperinsulinemic clamp with stable isotope labeled tracer infusion, magnetic resonance spectroscopy (MRS), and muscle biopsies. Following the two days of acute caloric restriction subjects will continue the same 50% kcal restricted diet untile they lose 5% of their initial body weight. Once subjects have achieved a 5% body weight loss, their total calorie intake will be adjusted to maintain constant body wieght and prevent further body loss. After subjects have maintained 5% weight loss for approximately 3 weeks, body composition analyses, baseline blood tests, and the isotope infustion study will be repeated.