title: Depot-specific adipocyte cell lines reveal differential drug-induced responses of white adipocytes--relevance for partial lipodystrophy.
abstract: 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/EBPbeta, 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 microg/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.
authors.affiliation: Dept. of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84103, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Kovsan
authors.forename: Alexander
authors.initials: A
authors.lastname: Osnis
authors.forename: Adva
authors.initials: A
authors.lastname: Maissel
authors.forename: Livnat
authors.initials: L
authors.lastname: Mazor
authors.forename: Tanya
authors.initials: T
authors.lastname: Tarnovscki
authors.forename: Liat
authors.initials: L
authors.lastname: Hollander
authors.forename: Shira
authors.initials: S
authors.lastname: Ovadia
authors.forename: Britta
authors.initials: B
authors.lastname: Meier
authors.forename: Johannes
authors.initials: J
authors.lastname: Klein
authors.forename: Nava
authors.initials: N
authors.lastname: Bashan
authors.forename: Assaf
authors.initials: A
authors.lastname: Rudich
mesh_terms: D052438:Adipocytes, White / Q000187:drug effects* / Q000502:physiology; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000273:Adipose Tissue / Q000166:cytology* / Q000187:drug effects; D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D050218:Body Fat Distribution; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D039682:HIV-Associated Lipodystrophy Syndrome / Q000209:etiology* / Q000473:pathology; D051379:Mice; D019888:Nelfinavir / Q000009:adverse effects / Q000494:pharmacology*; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019888:Nelfinavir