PMID- 19934369
OWN - NLM
STAT- MEDLINE
DCOM- 20091215
LR  - 20131121
IS  - 1535-3699 (Electronic)
IS  - 1535-3699 (Linking)
VI  - 234
IP  - 12
DP  - 2009 Dec
TI  - Impact of stimulatory pathways on adipogenesis and HIV-therapy associated 
      lipoatrophy.
PG  - 1484-92
LID - 10.3181/0907-RM-205 [doi]
AB  - OBJECTIVE: Current understanding of adipogenesis derives mainly from studies with 
      in vitro cell culture systems with divergent experimental requirements. We aimed 
      to investigate the discrepancy between the anti-adipogenic effects of the HIV 
      protease-inhibitor indinavir (IDV) in vitro and the lack of evidence that IDV 
      inhibits adipogenesis in humans. DESIGN AND METHODS: We studied cell viability 
      and adipogenesis in murine 3T3-F442A, 3T3-L1 and primary human subcutaneous 
      preadipocytes (phsPA). Differentiation was studied after activation of the 
      established four signalling pathways in different combinations. We analyzed 
      CCAAT/enhancer-binding protein (C/EBP) alpha and peroxisome 
      proliferator-activated receptor (PPAR) gamma expression and triacylglyceride 
      accumulation. Cells were exposed to IDV at concentrations around therapeutic 
      C(max) levels and higher (10 muM and 20 muM) for up to 30 days. RESULTS: Under 
      insulin and fetal calf serum (FCS) input, IDV inhibited 3T3-F442A 
      differentiation, an effect that was partially rescued by the addition of 
      3-isobutyl-1-methylxanthine (IBMX) stimulation. Combined stimulation with FCS, 
      insulin, dexamethasone (DEX) and IBMX led to normal 3T3-L1 differentiation even 
      in the presence of IDV. However, omission of IBMX rendered this cell line 
      sensitive to IDV's anti-adipogenic effects. Differentiation of phsPA requiring 
      complete adipogenic stimulation was not affected by IDV presence. CONCLUSIONS: 
      Our data suggest that the potency of IDV to impair differentiation under partial 
      stimulation disappears when all of the differentiation pathways are activated. 
      Such compensatory mechanisms might be responsible for the inability of the drug 
      to affect adipogenesis in vivo.
FAU - Stankov, Metodi V
AU  - Stankov MV
AD  - Clinic for Immunology and Rheumatology, Hannover Medical School, 
      Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
FAU - Schmidt, Reinhold E
AU  - Schmidt RE
FAU - Behrens, Georg M N
AU  - Behrens GM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Switzerland
TA  - Exp Biol Med (Maywood)
JT  - Experimental biology and medicine (Maywood, N.J.)
JID - 100973463
RN  - 0 (CCAAT-Enhancer-Binding Protein-alpha)
RN  - 0 (HIV Protease Inhibitors)
RN  - 0 (PPAR gamma)
RN  - 5W6YA9PKKH (Indinavir)
SB  - IM
MH  - 3T3-L1 Cells
MH  - Adipocytes/*metabolism
MH  - Adipogenesis/*drug effects
MH  - Animals
MH  - CCAAT-Enhancer-Binding Protein-alpha/biosynthesis
MH  - Cell Differentiation/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression Regulation/drug effects
MH  - *HIV
MH  - HIV Infections/*drug therapy/metabolism
MH  - HIV Protease Inhibitors/adverse effects/*pharmacology
MH  - Humans
MH  - Indinavir/adverse effects/*pharmacology
MH  - Mice
MH  - PPAR gamma/biosynthesis
EDAT- 2009/11/26 06:00
MHDA- 2009/12/16 06:00
CRDT- 2009/11/26 06:00
PHST- 2009/11/26 06:00 [entrez]
PHST- 2009/11/26 06:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
AID - 234/12/1484 [pii]
AID - 10.3181/0907-RM-205 [doi]
PST - ppublish
SO  - Exp Biol Med (Maywood). 2009 Dec;234(12):1484-92. doi: 10.3181/0907-RM-205.