Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity.
BACKGROUND
Angiotensin type 1 receptor (AT(1)R) blockers (ARB) have been shown to reduce the incidence of type 2 diabetes mellitus by an unknown molecular mechanism. The peroxisome proliferator-activated receptor-gamma (PPARgamma) is the central regulator of insulin and glucose metabolism improving insulin sensitivity. We investigated the regulation of PPARgamma function by ARBs.


RESULTS
The ARBs irbesartan and telmisartan (10 micromol/L) potently enhanced PPARgamma-dependent 3T3-L1 adipocyte differentiation associated with a significant increase in mRNA expression of the adipogenic marker gene adipose protein 2 (aP2), as measured by quantitative real-time polymerase chain reaction (irbesartan: 3.3+/-0.1-fold induction; telmisartan: 3.1+/-0.3-fold induction; both P<0.01). Telmisartan showed a more pronounced induction of aP2 expression in lower, pharmacologically relevant concentrations compared with the other ARBs. The ARB losartan enhanced aP2 expression only at high concentrations (losartan 100 micromol/L: 3.6+/-0.3-fold induction; P<0.01), whereas eprosartan up to 100 micromol/L had no significant effects. In transcription reporter assays, irbesartan and telmisartan (10 micromol/L) markedly induced transcriptional activity of PPARgamma by 3.4+/-0.9-fold and 2.6+/-0.6-fold (P<0.05), respectively, compared with 5.2+/-1.1-fold stimulation by the PPARgamma ligand pioglitazone (10 micromol/L). Irbesartan and telmisartan also induced PPARgamma activity in an AT1R-deficient cell model (PC12W), demonstrating that these ARBs stimulate PPARgamma activity independent of their AT(1)R blocking actions.


CONCLUSIONS
The present study demonstrates that a specific subset of ARBs induces PPARgamma activity, thereby promoting PPARgamma-dependent differentiation in adipocytes. The activation of PPARgamma demonstrates new pleiotropic actions of certain ARBs, providing a potential mechanism for their insulin-sensitizing/antidiabetic effects.
Schupp
Michael
M
Center for Cardiovascular Research, Institut für Pharmakologie und Toxikologie, Campus Charité-Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Janke
Jürgen
J
Clasen
Ronald
R
Unger
Thomas
T
Kintscher
Ulrich
U
D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000179:Acrylates / Q000494:pharmacology*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002454:Cell Differentiation; D017930:Genes, Reporter; D007093:Imidazoles / Q000494:pharmacology*; D007333:Insulin Resistance; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D047488:Retinoid X Receptors; D000077333:Telmisartan; D013777:Tetrazoles / Q000494:pharmacology*; D013876:Thiophenes; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics; D014162:Transfection
D000179:Acrylates; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D001713:Biphenyl Compounds; D007093:Imidazoles; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D013777:Tetrazoles; D013876:Thiophenes; D014157:Transcription Factors; C068373:eprosartan; D008156:Luciferases; D000077405:Irbesartan; D019808:Losartan; D000077333:Telmisartan