Regional Fatty Acid Metabolism In Humans

人类的区域脂肪酸代谢

基本信息

批准号：
8304350
负责人：
MICHAEL D. JENSEN
金额：
$ 57.75万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8304350
关键词：
1,2-diacylglycerol Abdomen Accounting Acetyltransferase Address Adipocytes Adipose tissue Adult Beds Biological Models Body Weight decreased Body fat Body part CD36 gene Cell model Cells Coenzyme A Ligases Data Diabetes Mellitus Diglycerides Etiology Fatty Acids Fatty acid glycerol esters Funding Goals Gonadal Steroid Hormones Health Heterogeneity Hormones Human Intracellular Transport Lead Leg Lipolysis Measures Mediating Metabolic Modeling Molecular Nonesterified Fatty Acids Obesity Pathway interactions Pattern Pharmaceutical Preparations Physiological Pioglitazone Plasma Population Process Proteins Role Shapes Site Sorting - Cell Movement Techniques Time Tissues Triglycerides Variant Visceral Woman disorder risk extracellular fatty acid metabolism fatty acid transport improved in vivo lipid biosynthesis lipoprotein lipase men public health relevance regional difference sex subcutaneous trafficking uptake

项目摘要

DESCRIPTION (provided by applicant): Regional differences in fat accumulation must develop from imbalances in fatty acid uptake or free fatty acid (FFA) release between fat depots. Our goal is to discover the etiology of regional differences in fat distribution between different types of obesity. We found that direct storage of circulating FFA independent of lipoprotein lipase seems to best relate to body fat distribution. During this funding cycle we sought to determine which steps in lipogenesis best relates to direct FFA storage by measuring direct FFA storage in lean and obese adults with a wide range of body fat distribution, as well as visceral adipose tissue FFA storage and the effects of sex steroids on adipose tissue fatty acid metabolism. We made the surprising discovery that plasma FFA concentrations are the best, and often the only, positive predictor of adipocyte FFA storage rates. This implies that increased adipocyte lipolysis and increases uptake and storage of circulating FFA go together despite an unfavorable concentration gradient. The cellular factors related to adipocyte lipogenesis that we measured: 1) facilitated inward transport (CD36, FATP-1); 2) activation of fatty acids via acyl-CoA synthetase (ACS); 3) triglyceride (TG) synthesis -mediated by diacylglycerol acetyltransferase (DGAT) were poorly predictive of FFA storage, and thus almost certainly not rate limiting. Our data leads us to propose that at low plasma FFA concentrations facilitated inwards fatty acid transport is the rate limiting step for fatty acid storage whereas the rate-limiting step at high plasma FFA concentrations may be an intracellular trafficking step. Recent findings regarding the heterogeneity of different sized adipocytes within the same tissue bed also suggests there could be heterogeneity with respect to fatty acid storage between large and small adipocytes. The specific aims of this proposal are to: 1. Assess whether direct FFA storage in subcutaneous adipose tissue is greater in small vs. large adipocytes within the same depot. 2. Determine whether adipose tissue FFA storage rates plateau at physiologically maximal plasma FFA concentrations, and if so whether maximal storage is related to transport (CD36/FATP-1), activation (ACS) or TG synthesis DGAT). 3. Examine whether variations in adipose tissue lipogenic factors, induced by weight loss or pioglitazone, alter regional FFA storage under conditions of low plasma FFA concentrations. 4. Examine whether alterations in adipose tissue lipogenic factors, induced by weight loss or pioglitazone, alter regional FFA storage under conditions of physiologically maximal plasma FFA concentrations. Completing these studies should provide firm evidence as to what types of cellular/molecular processes account for the physiologic observations and lead to productive models to improve regional fat storage from the perspective of metabolic health. PUBLIC HEALTH RELEVANCE: People who gain fat mostly in their abdomen are more likely to develop diabetes and other health problems. These studies are to better understand why adipose tissue in some parts of the body stores fat better than fat in other parts of the body. We will measure how fat storage is regulated by specific fat cell proteins in humans according to their body shape, hormone status, and whether they take medications for diabetes.

描述（由申请人提供）：脂肪积累的区域差异必定是由于脂肪库之间脂肪酸摄取或游离脂肪酸（FFA）释放的不平衡而产生的。我们的目标是发现不同类型肥胖之间脂肪分布区域差异的病因。我们发现，独立于脂蛋白脂肪酶的循环 FFA 的直接储存似乎与身体脂肪分布最相关。在这个资助周期中，我们试图通过测量具有广泛身体脂肪分布的瘦和肥胖成年人的直接 FFA 存储，以及内脏脂肪组织 FFA 存储和性别的影响，来确定脂肪生成中的哪些步骤与直接 FFA 存储最相关。类固醇对脂肪组织脂肪酸代谢的影响。我们令人惊讶地发现，血浆 FFA 浓度是脂肪细胞 FFA 储存率的最佳且通常是唯一的阳性预测因子。这意味着尽管存在不利的浓度梯度，但脂肪细胞脂肪分解的增加和循环 FFA 的吸收和储存的增加是相辅相成的。我们测量的与脂肪细胞脂肪生成相关的细胞因素：1）促进向内运输（CD36、FATP-1）； 2)通过酰基辅酶A合成酶(ACS)激活脂肪酸； 3) 由二酰基甘油乙酰转移酶 (DGAT) 介导的甘油三酯 (TG) 合成对 FFA 储存的预测效果较差，因此几乎肯定不会限制速率。我们的数据使我们提出，在低血浆 FFA 浓度下促进脂肪酸向内转运是脂肪酸储存的限速步骤，而在高血浆 FFA 浓度下的限速步骤可能是细胞内运输步骤。关于同一组织床内不同大小脂肪细胞异质性的最新发现也表明，大脂肪细胞和小脂肪细胞之间的脂肪酸储存可能存在异质性。该提案的具体目标是： 1. 评估同一储存库中小脂肪细胞与大脂肪细胞皮下脂肪组织中的直接 FFA 储存是否更大。 2. 确定脂肪组织 FFA 储存率是否在生理最大血浆 FFA 浓度处达到稳定水平，如果是，则最大储存量是否与转运 (CD36/FATP-1)、激活 (ACS) 或 TG 合成 DGAT) 有关。 3. 检查由减肥或吡格列酮引起的脂肪组织脂肪生成因子的变化是否会改变低血浆 FFA 浓度条件下的局部 FFA 储存。 4. 检查由体重减轻或吡格列酮引起的脂肪组织脂肪生成因子的改变是否会改变生理学最大血浆FFA浓度条件下的局部FFA储存。完成这些研究应该为哪些类型的细胞/分子过程解释生理观察提供确凿的证据，并产生有效的模型，从代谢健康的角度改善区域脂肪储存。公众健康相关性：腹部脂肪主要增加的人更有可能患糖尿病和其他健康问题。这些研究是为了更好地理解为什么身体某些部位的脂肪组织比身体其他部位的脂肪更好地储存脂肪。我们将根据人体形状、激素状态以及是否服用糖尿病药物来测量人体特定脂肪细胞蛋白如何调节脂肪储存。