PORTAL VENOUS FATTY ACIDS AS A DETERMINANT OF BLOOD PRESSURE

肥胖显著增加了患高血压的风险，但导致肥胖相关高血压的机制知之甚少。本研究的长期目标是评估非酯化脂肪酸（NEFA）在肥胖相关高血压发生中的作用。特别是，内脏生产NEFA和血压调节之间的关系将进行探讨。提出了四个具体目标。将确定瘦个体和内脏和下半身肥胖受试者的内脏和全身NEFA产生、交感神经活性和血压之间的关系。NEFA生产在这些人的抑制性也将比较交感神经活动的测量。将评估饮食诱导的体重减轻和药物治疗对内脏和全身NEFA产生、交感神经活性和血压的影响。将对90名妇女进行研究。将研究30名瘦对照受试者、30名下半身肥胖个体和30名上半身肥胖个体。将使用DEXA和CT扫描表征体脂分布，并使用动态监测评估血压。内脏和全身NEFA的产生将通过在肝静脉导管插入术后输注3 H-棕榈酸酯来确定。将测量肾去甲肾上腺素（NE）溢出，并使用去甲肾上腺素（NE）溢出的动力学分析估计NE产生。将测量去甲肾上腺素（NE）溢出，并使用输注3 H-NE衰减的动力学分析估计NE产生。将在高胰岛素、正葡萄糖钳夹研究期间确定NEFA产生的抑制性。在钳夹研究期间，将重复测量NEFA产生和NE动力学。30名妇女将接受为期16周的监督减肥计划，每周与营养师和饮食监督会面。体重减轻计划完成后，将测量身体组成、血压、NEFA产生和抑制性以及NE溢出和动力学，以确定体重减轻的过度影响与NEFA代谢变化之间的关系。第二项干预研究将在第三名女性中进行，以测试药物降低NEFA产生对血压和NE动力学的影响。个体将接受尼古丁酸和曲格列酮治疗，以将空腹NEFA水平降低50%。将在药物干预结束时重复研究。综上所述，这些研究应该提供有关内脏NEFA在肥胖相关高血压发生中的作用的信息。

Obesity markedly increases the risk of developing hypertension, but the mechanisms which lead to obesity-related hypertension are poorly understood. The long-term objectives of this proposal are to evaluate the role of non-esterified fatty acids (NEFA) in the genesis of obesity-related hypertension. In particular, the relationship between splanchnic production of NEFA and blood pressure regulation will be explored. Four specific aims are proposed. The relationship between splanchnic and systemic NEFA production, sympathetic nerve activity and blood pressure in lean individuals and subjects with visceral and lower body obesity will be determined. The suppressibility of NEFA production in these individuals will also be compared to measurements of sympathetic activity. The effects of dietary induced weight reduction and pharmacologic therapy on splanchnic and systemic NEFA production, sympathetic nerve activity and blood pressure will be assessed. Ninety women will be studied. Thirty lean control subjects, thirty individuals with lower body obesity and thirty individuals with upper obesity will be studied. Body fat distribution will be characterized using DEXA and CT scanning and blood pressure will be assessed using ambulatory monitoring. Splanchnic and systemic NEFA production will be determined using infusions of 3H-palmitate following hepatic venous catheterization. Renal norepinephrine (NE) spillover will be measured and NE production will be estimated using kinetic analysis of norepinephrine (NE) spillover will be measured and NE production will be estimated using kinetic analysis of the decay of infused 3H-NE. Suppressibility of NEFA production will be determined during a hyperinsulinemic, euglycemic clamp study. Measurements of both NEFA production and NE kinetics will be repeated during the clamp study. Thirty women will undergo a sixteen week supervised weight loss program entailing weekly meetings with a dietitian and dietary supervision. Body composition, blood pressure, NEFA production and suppressibility and NE spillover and kinetics will be measured after completion of the weight loss program to determine the relationship between the hypotensive effects of weight loss and changes in NEFA metabolism. A second intervention study will be performed in third women to test the effects of pharmacologic lowering of NEFA production on blood pressure and NE kinetics. Individuals will be treated with nicotine acid and troglitazone to reduce fasting NEFA levels by 50%. Studies will be repeated at the conclusion of the pharmacologic intervention. Taken together, these studies should provide information regarding the role of splanchnic NEFA in the genesis of obesity-related hypertension.