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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/E315    most recent 90486.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kovsan, J. Articles by Rudich, A. Search for Related Content PubMed PubMed Citation Articles by Kovsan, J. Articles by Rudich, A.

Depot-specific adipocyte cell lines reveal differential drug-induced responses of white adipocytes—relevance for partial lipodystrophy

¹Department of Clinical Biochemistry, Ben-Gurion University, Beer-Sheva, Israel; ²Department of Internal Medicine I, University of Lübeck, Lübeck, Germany; and ³The International Center for Health and Nutrition, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel

Submitted 3 June 2008 ; accepted in final form 19 November 2008

Intra-abdominal (IA) fat functionally differs from subcutaneous (SC) adipose tissue, likely contributing to its stronger association with obesity-induced morbidity and to differential response to medications. Drug-induced partial lipodystrophy, like in response to antiretroviral agents, is an extreme manifestation of the different response of different fat depots, with loss of SC but not IA. Investigating depot-specific adipocyte differences is limited by the low accessibility to IA fat and by the heterogenous cell population comprising adipose tissue. Here, we aimed at utilizing immortalized preadipocyte cell lines from IA (epididymal) or SC (inguinal) fat to investigate whether they differentially respond to the HIV protease inhibitor nelfinavir. Preadipocytes were readily amenable to adipogenesis, as evidenced by lipid accumulation, expression of adipose-specific genes, measurable lipolysis, and insulin responsiveness. Leptin secretion was higher by the SC line, consistent with known differences between IA and SC fat. As previously reported, nelfinavir inhibited adipogenesis downstream of C/EBPβ, but similarly in both cell lines. In contrast, nelfinavir's capacity to diminish insulin signaling, decrease leptin secretion, enhance basal lipolysis, and decrease expression of the lipid droplet-associated protein perilipin occurred more robustly and/or at lower nelfinavir concentrations in the SC line. This was despite similar intracellular concentrations of nelfinavir (23.8 ± 5.6 and 33.6 ± 12.2 µg/mg protein for inguinal and epididymal adipocytes, respectively, P = 0.46). The cell lines recapitulated depot-differential effects of nelfinavir observed in differentiated primary preadipocytes and with whole tissue explants. Thus, we report the use of fat depot-specific adipocyte cell lines for unraveling depot-differential responses to a drug causing partial lipodystrophy.

nelfinavir; lipolysis; perilipin; intra-abdominal adipocytes; subcutaneous adipocytes