Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator.
Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.
Berger
Joel P
JP
RY80N-C31, Merck Research Laboratories, 126 East Lincoln Avenue, Rahway, New Jersey 07065, USA. joel_berger@merck.com.
Petro
Ann E
AE
Macnaul
Karen L
KL
Kelly
Linda J
LJ
Zhang
Bei B
BB
Richards
Karen
K
Elbrecht
Alex
A
Johnson
Bruce A
BA
Zhou
Gaochao
G
Doebber
Thomas W
TW
Biswas
Chhabi
C
Parikh
Mona
M
Sharma
Neelam
N
Tanen
Michael R
MR
Thompson
G Marie
GM
Ventre
John
J
Adams
Alan D
AD
Mosley
Ralph
R
Surwit
Richard S
RS
Moller
David E
DE
D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006943:Hyperglycemia / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology*; D007333:Insulin Resistance; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000737:chemistry*; D013440:Sulfides / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists* / Q000737:chemistry*; D015430:Weight Gain / Q000187:drug effects
C479635:5-chloro-1-(4-chlorobenzyl)-3-(phenylthio)indole-2-carboxylic acid; D007211:Indoles; D018160:Receptors, Cytoplasmic and Nuclear; D013440:Sulfides; D014157:Transcription Factors