MENOPAUSE, LPL GENOTYPE AND METABOLISM AFTER WEIGHT LOSS

本研究旨在确定具有脂蛋白脂肪酶（LPL） PvuII基因共同多态性（即（+）等位基因）的肥胖绝经后妇女是否比没有LPL PvuII切割位点（-/-）的妇女对减肥（WL）治疗的代谢反应更不利。假设LPL PvuII基因型以剂量依赖的方式影响禁食肌肉和脂肪组织、LPL活性以及低热量喂养诱导的WL的代谢反应，从而影响绝经后妇女WL后总脂肪和内脏脂肪减少的幅度，以及葡萄糖/胰岛素和脂蛋白脂代谢的改善。具体目的是确定低热量饮食中LPL pvii（+）切割位点纯合子的肥胖女性，即（+/+）基因型是否比杂合子的肥胖女性脂肪组织LPL增加更多，肌肉LPL活动减少，静息代谢率（RMR）和脂肪氧化下降更大，这与：1)总体和内脏脂肪减少较少；2)脂质和葡萄糖代谢的改善比没有切割部位的妇女要小，即（-/-）。我们将研究健康，肥胖（身体质量指数，30-40 kg/m2） 50-60岁绝经5年内的妇女。检验我们假设的统计能力是基于初步数据，显示脂肪组织LPL对WL的反应在LPL pvii（+/+）和（-/-）基因型之间存在差异，并且需要27名女性/基因型。受试者将根据LPL基因型进行前瞻性研究，以确保研究的肥胖绝经妇女是同质的，以消除性别、年龄、绝经持续时间和身体组成等混杂因素对WL治疗代谢反应的影响。代谢研究是在基线和6个月后的2-3周内对准备好的、计算体重的、维持热量的饮食进行的，以确保代谢稳定；在短期研究后对低热量饮食进行的，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的LPL活性、RMR、脂肪氧化、总脂肪和内脏脂肪（DXA和CT扫描）脂蛋白脂和。口服葡萄糖耐量试验期间的葡萄糖/胰岛素反应。在wl后的代谢评估之后，受试者进入6个月的随访期，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女性倾向于从WL中获得更有利的代谢健康益处的基因代谢机制来增强我们对肥胖的理解。这将允许针对更有可能反应的女性进行WL治疗，并针对那些不太可能对WL反应的女性进行药物和其他治疗。这一乐观结果将降低老年妇女肥胖患病率和心血管疾病风险。

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.