Regional differences in the response of human pre-adipocytes to PPARgamma and RXRalpha agonists.
We have previously reported that omental (OM) preadipocytes respond less well to the prodifferentiating effects of thiazolidinediones than do preadipocytes from subcutaneous (SC) depots. This finding is consistent with in vivo alterations in fat distribution that occur in humans treated with thiazolidinediones. To explore these site-related differences further, we used real-time RT-PCR to quantify the specific mRNAs encoding peroxisome proliferator-activated receptor (PPAR) gamma1 and gamma2 and found that both isoforms were more highly expressed in SC than in OM preadipocytes. After 10 days of thiazolidinedione treatment, preadipocytes from both depots showed a small and comparable increase in expression of PPARgamma1 mRNA (1.7 +/- 0.2-fold [P = 0.007]) and 1.3 +/- 0.1-fold [P = 0.008] increase for SC and OM, respectively). There was a much larger increase in PPARgamma2 expression, which was significantly greater in SC compared with OM preadipocytes (11.1 +/- 2.8-fold [P = 0.0003] and 5.5 +/- 1.7-fold [P = 0.0003], respectively; P = 0.014 for SC versus OM). To establish whether the refractoriness of OM preadipocytes to differentiation was unique to activators of the PPARgamma pathway, we examined the effects of the retinoid X receptor (RXR) ligand LG100268. As assessed by glycerol-3-phosphate dehydrogenase activity, LG100268 had a greater effect on the differentiation of SC compared with OM preadipocytes when examined alone (SC = 5.7 +/- 1.7-fold vs. OM = 1.9 +/- 0.6-fold; P < 0.05) or in combination with rosiglitazone (SC = 27.0 +/- 7.5 vs. OM = 10.6 +/- 3.6-fold; P < 0.05). Consistent with this, RXRalpha mRNA levels were also higher in SC than in OM preadipocytes. In summary, the previously reported insensitivity of OM preadipocytes to the differentiating effects of thiazolidinediones may relate to their lower basal levels of PPARgamma1 and gamma2 mRNA and their diminished capacity to upregulate PPARgamma2 expression in response to ligand. That omentally derived cells also show reduced responsiveness to the prodifferentiating actions of an RXR ligand and a lower expression of RXRalpha in the undifferentiated state suggests that they may have a more generalized resistance to differentiation.
Sewter
Ciaran P
CP
University of Cambridge, Departments of Medicine and Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom.
Blows
Fiona
F
Vidal-Puig
Antonio
A
O'Rahilly
Stephen
S
D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000328:Adult; D000368:Aged; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D009539:Nicotinic Acids / Q000494:pharmacology; D009852:Omentum; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000235:genetics; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D012867:Skin; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics
D007004:Hypoglycemic Agents; D008024:Ligands; D009539:Nicotinic Acids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione; C095104:LG 100268