ADIPOCYTE TURNOVER AND METABOLISM IN HIV-1 LIPOATROPHY

描述（改编自申请人摘要） 皮下脂肪的损失或脂肪萎缩（LA），是一个重要的，但不好 了解HIV-1感染者的问题。 近期临床研究 提示存在两种与抗逆转录病毒（ARV）相关的LA综合征 治疗：蛋白酶抑制剂（PI）相关和核苷逆转录- 酶抑制剂（NRTI）相关。 脂肪损失的性质（减少脂肪细胞 数量或每个脂肪细胞的脂质含量）及其潜在的代谢/动力学 基础（脂肪细胞的破坏或再生减少， 前脂肪细胞池大小或分化，和/或脂肪细胞中的变化 脂肪生成或脂肪分解）仍然未知。 是否发生脂肪细胞更新 在正常人体生理学或LA综合征中的作用尚未确定。 的 这些研究的主要目的是了解脂肪细胞的作用 LA中的周转（增殖、前脂肪细胞分化和死亡） 综合征 第二个目标是建立脂肪组织之间的联系 动力学或质量和中间代谢的改变。 现在 可以直接在人体内测量细胞增殖，通过标记 脱氧核糖部分的DNA在分裂的细胞，与2 H-葡萄糖。 这种技术 已被修改为长期研究的慢周转细胞，如 脂肪细胞，通过给药2 H2O。 在人类受试者中进行的初步研究 证实了在成熟脂肪细胞和基质血管细胞中的增殖， 脂肪组织 将进行脂肪组织动力学的横断面研究 在健康HIV-1感染者（n=12）或NRTI相关（n=12）中进行 综合征 纵向研究也将进行之前和期间的两个 使用PI-（n=18）为基础的方案进行ARV治疗年，以确定时间进程， 脂肪组织变化的频率和相关性。 增殖与池化 前脂肪细胞的大小将通过使用前脂肪细胞因子-1 （表-1）。 肝脏胰岛素抵抗和极低密度脂蛋白-甘油三酯代谢将是 同时测量。 总之，了解脂肪组织的必要性 人类抗逆转录病毒前脂肪细胞更新的动力学。 基础和临床 关于脂肪组织的周转和功能的重要问题可以 解决，以提高对自然历史，可逆性， 抗逆转录病毒相关的临床分类和潜在的治疗策略 路易斯安那州

DESCRIPTION (Adapted from the applicant's abstract) The loss of subcutaneous fat or lipoatrophy (LA), is an important but poorly understood problem in HIV-1 infected patients. Recent clinical studies suggest the existence of two LA syndromes associated with antiretroviral (ARV) therapy: protease inhibitor (PI)-associated and nucleoside reverse transcrip- tase inhibitor (NRTI)-associated. The nature of fat loss (reduced adipocyte number or lipid content per fat cell) and its underlying metabolic/kinetic basis (destruction or reduced regeneration of fat cells, changes in preadipocyte pool size or differentiation, and/or changes in adipocyte lipogenesis or lipolysis) remain unknown. Whether adipocyte turnover occurs in normal human physiology or LA syndromes has not been determined. The primary objective of these studies is to understand the role of adipocyte turnover (proliferation, differentiation from preadipocytes, and death) in LA syndromes. A second goal is to establish connections between adipose tissue kinetics or mass and alterations in intermediary metabolism. It is now possible to measure cell proliferation directly in humans, by labeling the deoxyribose moiety of DNA in dividing cells, with 2H-glucose. This technique has been modified for long-term studies of slow turnover cells, such as adipocytes, by administration of 2H2O. Pilot studies in human subjects have confirmed proliferation in mature adipocytes and stromal-vascular cells from adipose tissue. Cross-sectional studies of adipose tissue kinetics will be performed in health HIV-1 infected persons (n=12) or NRTI-associated (n=12) syndromes. A longitudinal study will also be performed before and during two years of ARV therapy with PI-(n=18) based regimens, to establish time course, frequency and correlates of adipose tissue changes. Proliferation and pool size of preadipocytes will be determined by use of preadipocyte factor-1 (pref-1). Hepatic insulin resistance and VLDL-triglyceride metabolism will be measured concurrently. In summary, the need to understand adipose tissue kinetics in ARV-preadipocyte turnover in humans. Basic and clinically important questions concerning the turnover and function of adipose tissue can be addressed, to improve understanding of natural history, reversibility, clinical classification and potential treatment strategies for ARV-associated LA.