![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
CELLULAR AND MOLECULAR
Is a Potent Antidiabetic Thiazolidinedione Yet Weakly Adipogenic
Discovery Research, Dr. Reddy's Laboratories Ltd., Miyapur, Hyderabad, India (P.M., R.C., R.K.V., G.B., S.J., J.H., C.G., A.R., R.R.); and Department of Pathology Northwestern University, The Feinberg School of Medicine, Chicago, Illinois (P.M., P.K., S.Y., S.S., C.Q., Y.J.Z., M.S.R., J.K.R.).
PAT5A [5-[4-[N-(2-pyridyl)-(2S)-pyrrolidine-2-methoxyl]phenylmethylene[thiazolidine-2,4-dione, malic acid salt]], a chemically distinct unsaturated thiazolidinedione, activates peroxisome proliferator-activated receptor 
(PPAR) submaximally in vitro with the binding affinity 
10 times less than that of rosiglitazone, a highly potent thiazolidinedione. PAT5A reduces plasma glucose level and improves insulin sensitivity in insulin resistant db/db mice, similar to that of rosiglitazone, while exerting a relatively weak adipogenic effect. In contrast to rosiglitazone, PAT5A inhibits cholesterol and fatty acid biosynthesis suggesting that PAT5A possesses a unique receptor-independent non-PPAR related property. PAT5A induces qualitatively similar but quantitatively different protease digestion patterns and interacts with PPAR differently than rosiglitazone. PAT5A shows differential cofactor recruitment and gene activation than that of rosiglitazone. Thus, the partial agonism of PAT5A to PPAR together with its receptor independent effects may contribute to its antidiabetic potency similar to rosiglitazone in vivo despite reduced affinity for PPAR. These biological effects suggest that PAT5A is a PPAR modulator that activates some (insulin sensitization), but not all (adipogenesis), PPAR-signaling pathways.
Address correspondence to: Dr. Rajagopalan Ramanujam, Discovery Research, Dr. Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad: 500050, India. E-mail: rajagopalanr{at}drreddys.com
This article has been cited by other articles:
|
|
 |
|
  O. Ziouzenkova, G. Orasanu, G. Sukhova, E. Lau, J. P. Berger, G. Tang, N. I. Krinsky, G. G. Dolnikowski, and J. Plutzky Asymmetric Cleavage of {beta}-Carotene Yields a Transcriptional Repressor of Retinoid X Receptor and Peroxisome Proliferator-Activated Receptor Responses Mol. Endocrinol., January 1, 2007; 21(1): 77 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Michalik, J. Auwerx, J. P. Berger, V. K. Chatterjee, C. K. Glass, F. J. Gonzalez, P. A. Grimaldi, T. Kadowaki, M. A. Lazar, S. O'Rahilly, et al. International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors Pharmacol. Rev., December 1, 2006; 58(4): 726 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Gilde, J.-C. Fruchart, and B. Staels Peroxisome Proliferator-Activated Receptors at the Crossroads of Obesity, Diabetes, and Cardiovascular Disease J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A24 - A32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Allen, F. Zhang, S. A. Moodie, L. E. Clemens, A. Smith, F. Gregoire, A. Bell, G. E.O. Muscat, and T. A. Gustafson Halofenate Is a Selective Peroxisome Proliferator-Activated Receptor {gamma} Modulator With Antidiabetic Activity Diabetes, September 1, 2006; 55(9): 2523 - 2533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Burgermeister, A. Schnoebelen, A. Flament, J. Benz, M. Stihle, B. Gsell, A. Rufer, A. Ruf, B. Kuhn, H. P. Marki, et al. A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor-{gamma} (PPAR{gamma}) Recruits PPAR{gamma}-Coactivator-1{alpha}, Prevents Triglyceride Accumulation, and Potentiates Insulin Signaling in Vitro Mol. Endocrinol., April 1, 2006; 20(4): 809 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Knouff and J. Auwerx Peroxisome Proliferator-Activated Receptor-{gamma} Calls for Activation in Moderation: Lessons from Genetics and Pharmacology Endocr. Rev., December 1, 2004; 25(6): 899 - 918. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
