ADIPOCYTE TURNOVER AND METABOLISM IN HIV-1 LIPOATROPHY

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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.