ACUTE AND CHRONIC CALORIE RESTRICTION AND THE METABOLIC SYNDROME

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。胰岛素抵抗是代谢综合征的一个潜在特征，与内皮功能障碍和冠心病有关。减肥可改善肥胖患者的胰岛素敏感性、内皮功能和代谢综合征的所有特征。此外，在没有显著体重减轻的情况下，短期限制卡路里摄入可以改善胰岛素的作用。然而，急性卡路里限制导致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导致了有益效果，目前尚不清楚。此外，短期热量限制是否能改善内皮功能尚不清楚。因此，本项目的主要目标是评估急性和慢性卡路里限制对代谢综合征受试者中参与血管疾病发病机制的胰岛素敏感性和炎症两个关键因素的影响的潜在机制。我们假设短期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（>=120 g/d）改善胰岛素作用、炎症和内皮功能（血管疾病的标志），而急性热量限制与低碳水化合物摄入（<=40 g/d）将损害这些参数，因为脂肪酸通量增加。我们还提出，适度减肥，无论是低脂饮食还是低碳水化合物饮食，由于基因表达的长期改变，短期热量限制对胰岛素作用、炎症和内皮功能有更大的有益影响。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，可以为患有代谢综合征的肥胖患者提供更有效的治疗策略。40名（BMI 30-45 kg/ms）受试者将被随机分配接受低热量饮食，其中碳水化合物含量充足（>=120 g/d）或较低（<=40 g/d）。该饮食将提供50%的卡路里不足，包括身体成分的前和姿势测量，稳定同位素标记示踪剂输注的两阶段正糖高胰岛素钳夹，磁共振波谱（MRS）和肌肉活检。在两天的急性热量限制之后，受试者将继续同样的50%卡路里限制饮食，直到他们减掉了最初体重的5%。一旦受试者达到5%的体重减轻，他们的总热量摄入将被调整，以保持恒定的体重，防止进一步的体重减轻。在受试者保持5%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.