MENOPAUSE, LPL GENOTYPE AND METABOLISM AFTER WEIGHT LOSS

本研究旨在确定脂蛋白脂酶（LPL）PvuII基因中具有常见多态性（即（+）等位基因）的绝经后肥胖女性对减肥（WL）治疗的代谢反应是否低于无LPL PvuII切割位点（-/-）的女性。 该假设是，LPL PvuII基因型影响空腹肌肉和脂肪组织和LPL活性和低热量喂养诱导WL的代谢反应，以剂量依赖的方式影响总脂肪和内脏脂肪减少的幅度，以及改善葡萄糖/胰岛素和脂蛋白脂质代谢后WL在绝经后妇女。 具体的目的是确定在低热量饮食期间，对于LPL PvuII（+）切割位点纯合的肥胖妇女，即（+/+）基因型，是否比杂合子具有更大的脂肪组织LPL增加和肌肉LPL活性降低以及更大的静息代谢率（RMR）和脂肪氧化降低，这与：1）更少的全身和内脏脂肪损失;和2）与没有切割部位的妇女相比，脂质和葡萄糖代谢的改善较小，即，(-/-). 我们将研究绝经5年内的健康、肥胖（体重指数，30-40 kg/m2）的50-60岁女性。 检验我们的假设的统计功效是基于初步数据，该数据显示LPL PvuII（+/+）和（-/-）基因型之间脂肪组织LPL对WL的反应存在差异，并且需要27名女性/基因型。 受试者将基于其LPL基因型前瞻性入组，以确保研究肥胖绝经女性的同质组，以消除性别、年龄、绝经持续时间和身体组成对WL治疗代谢反应的混杂因素。 在基线和6个月WL后对制备的计算体重维持正常热量饮食2-3周进行代谢研究以确保代谢稳定性，并在短期研究后对低热量饮食进行代谢研究以评估对负能量平衡的代谢反应。 我们将测量肌肉和脂肪组织LPL活性，RMR，脂肪氧化，总脂肪和内脏脂肪（DXA和CT扫描）脂蛋白脂质和。口服葡萄糖耐量试验期间的葡萄糖/胰岛素反应。在WL后代谢评估之后，受试者进入6个月随访期，随后进行代谢测试以评估基因型的长期代谢适应和体重恢复。总的来说，这些发现将通过评估一些肥胖妇女从WL获得更有利的代谢健康益处的易感性的基因代谢机制来增强我们对肥胖的理解。 这将使WL治疗的目标更有可能响应的妇女，和药物和其他治疗那些不太可能响应WL。 这一乐观的结果将降低肥胖的患病率和老年妇女心血管疾病的风险。

This research is designed to determine whether obese postmenopausal women with a common polymorphism in the lipoprotein lipase (LPL) PvuII gene, i.e. the (+) allele have less favorable metabolic responses to weight loss (WL) treatment than women without the LPL PvuII cut-site (-/-). The hypothesis is that the LPL PvuII genotype affects fasting muscle and adipose tissue and LPL activity and the metabolic responses to hypocaloric feeding-induced WL in a dose-dependent manner to affect the magnitude of the reduction of total and visceral fat, and improvements in glucose/insulin and lipoprotein lipid metabolism following WL in postmenopausal women. Specific aims determine whether obese women who are homozygous for the LPL PvuII (+) cut-site, i.e. the (+/+) genotype, have greater increases in adipose tissue LPL and decreases in muscle LPL activity and larger decreases in resting metabolic rate (RMR) and fat oxidation than heterozygotes during hypocaloric diets, that are associated with: 1) the loss of less total body and visceral fat; and 2) smaller improvements in lipid and glucose metabolism than women without the cut-site, i.e., (-/-). We will study healthy, obese (Body Mass Index, 30-40 kg/m2) 50-60 year old women within 5 years of menopause. The statistical power to test our hypothesis is based on preliminary data showing differences in adipose tissue LPL responses to WL between LPL PvuII (+/+) and (-/-) genotypes, and requires 27 women/genotype. Subjects will be entered prospectively based on their LPL genotype to ensure a homogeneous group of obese menopausal women are studied to eliminate confounding factors of gender, age, duration from menopause and body composition on the metabolic responses to WL treatment. Metabolic studies are performed on prepared calculated weight maintaining eucaloric diets for 2-3 weeks at baseline and after 6-mo WL to ensure metabolic stability, and on hypocaloric diets after the short-term study to assess metabolic responses to negative energy balance. We will measure muscle and adipose tissue LPL activity, RMR, fat oxidation, total and visceral body fat (DXA and CT scans) lipoprotein lipids and. glucose/insulin responses during an oral glucose tolerance test. Following the post-WL metabolic evaluations, subjects enter a 6- mo follow-up period followed by metabolic testing to assess long- term metabolic adaptations and weight regain by genotype. Collectively, these findings will enhance our understanding of obesity by assessing the gene-metabolic mechanisms underlying the predisposition of some obese women to more favorable metabolic health benefits from WL. This would allow the targeting of WL treatments to women more likely to respond, and pharmacologic and other treatments to those less likely to respond to WL. This optimistic outcome would reduce prevalence of obesity and risk for CVD in older women.