Angiotensin type 1 receptor antagonists induce human in-vitro adipogenesis through peroxisome proliferator-activated receptor-gamma activation.
OBJECTIVE
In clonal animal cells, certain angiotensin receptor blockers (ARB) activate the peroxisome proliferator-activated receptor-gamma (PPARgamma). The aim of this work was to validate that observation in human cells and humans.


METHODS
We investigated the induction of in-vitro adipogenesis and the activation of PPARgamma-target genes, adiponectin and lipoprotein lipase, by ARB in human preadipocytes. We also studied PPARgamma response-element-driven luciferase reporter gene activation in human adipocytes. Finally, we treated 14 obese men for 10 days with placebo crossed over with 150 mg/day irbesartan. Subcutaneous fat was analyzed for mRNA expression of adiponectin and lipoprotein lipase.


RESULTS
Telmisartan and irbesartan, and to a lesser degree losartan, induced adipogenesis and activated PPARgamma-target genes. This stimulation of PPARgamma-target genes was prevented by the PPARgamma antagonist GW9662. Eprosartan had no effect. Paradoxically, all ARB activated the luciferase reporter gene. PPARgamma activity increased approximately two-fold with pioglitazone and 1.5-fold with the ARB in all assays. In the cross-over clinical study, irbesartan lowered blood pressure but had no effect on adiponectin or lipoprotein lipase mRNA expression.


CONCLUSIONS
Our data are the first to show that ARB induce adipogenesis and PPARgamma-target gene expression in human adipocytes. Pharmacokinetic differences may contribute to the heterogeneous effects on metabolism and preadipocyte differentiation. In humans, larger doses of ARB, longer treatments, or both may be required to activate PPARgamma in adipose cells.
Janke
Jürgen
J
Medical Faculty of the Charité, Franz Volhard Clinic, HELIOS Klinikum-Berlin, Berlin, Germany. juergen.janke@charite.de
Schupp
Michael
M
Engeli
Stefan
S
Gorzelniak
Kerstin
K
Boschmann
Michael
M
Sauma
Lilian
L
Nystrom
Fredrik H
FH
Jordan
Jens
J
Luft
Friedrich C
FC
Sharma
Arya M
AM
D050156:Adipogenesis; D052242:Adiponectin / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D006801:Humans; D000077405:Irbesartan; D008071:Lipoprotein Lipase / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
D052242:Adiponectin; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D047495:PPAR gamma; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D045162:Thiazolidinediones; D008156:Luciferases; D008071:Lipoprotein Lipase; D000077405:Irbesartan; D019808:Losartan; D000077333:Telmisartan; D000077205:Pioglitazone