help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Way, J. M.
Right arrow Articles by Kliewer, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Way, J. M.
Right arrow Articles by Kliewer, S. A.
Endocrinology Vol. 142, No. 3 1269-1277
Copyright © 2001 by The Endocrine Society

ARTICLES

Comprehensive Messenger Ribonucleic Acid Profiling Reveals That Peroxisome Proliferator-Activated Receptor {gamma} Activation Has Coordinate Effects on Gene Expression in Multiple Insulin-Sensitive Tissues

James M. Way, W. Wallace Harrington, Kathleen K. Brown, William K. Gottschalk, Scott S. Sundseth, Traci A. Mansfield, Ravi K. Ramachandran, Timothy M. Willson and Steven A. Kliewer

Departments of Molecular Endocrinology (J.M.W., S.A.K.), Metabolic Diseases (W.W.H., K.K.B., W.K.G.), Discovery Genetics (S.S.S.), and Medicinal Chemistry (T.M.W.), Glaxo Wellcome Inc., Research and Development, Research Triangle Park, North Carolina 27709; and CuraGen Corp. (T.A.M., R.K.R.), New Haven, Connecticut 06511

Address all correspondence and requests for reprints to: Dr. Steven A. Kliewer, Glaxo Wellcome Inc. Research and Development, Venture 118, 5 Moore Drive, Research Triangle Park, North Carolina 27709. E-mail: sak15922{at}glaxowellcome.com

Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR{gamma} ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR{gamma} in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR{gamma} activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR{gamma} agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR{gamma}-mediated increases in glucose utilization in muscle. In liver, PPAR{gamma} activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR{gamma} agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2001 by The Endocrine Society