Diabetes, Vol 49, Issue 12 2108-2115, Copyright © 2000 by American Diabetes Association

ARTICLES

Thiazolidinediones inhibit the expression of beta3-adrenergic receptors at a transcriptional level

E Bakopanos and JE Silva
Lady Davis Institute for Medical Research, Division of Endocrinology and Metabolism, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

The effect of the thiazolidinediones (TZDs) darglitazone and troglitazone on beta3-adrenergic receptor (AR) expression was studied in cultured cell lines representing several tissues. After 24 h of exposing HIB-1B brown adipocytes to 30 micromol/l darglitazone or 20 micromol/l troglitazone, beta3-AR mRNA levels were reduced by 75%. This effect was significant within 1 h of exposure to a maximal dose of these drugs, with the full effect obtained within 10 h. The darglitazone ID50 was approximately 10 nmol/l, similar to the Kd of TZDs binding to peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These drugs also decreased beta3-AR mRNA in 3T3-F442A white adipocytes, but not in SK-N-MC cells, which lack PPAR-gamma2. A luciferase reporter gene containing 1.4 kb of 5' flanking sequence of the mouse beta3-AR was transiently transfected, with or without PPAR-gamma2, in SK-N-MC cells. The vigorous expression of luciferase driven by the beta3-AR gene sequence was inhibited by TZDs in a PPAR-gamma2-dependent manner. The half-lives of gamma3-AR precursor RNA and mRNA were short, approximately 40 and approximately 100 min, respectively, and remained unaffected by TZD treatment. Exposure of HIB-1B cells to 30 micromol/l darglitazone was associated with reduced beta3-AR mRNA levels, as well as decreased response of uncoupling protein 1 to norepinephrine + propranolol (a beta1 beta2-AR antagonist) or the specific beta3-AR agonist CL 316, 243. Both the beta3-AR mRNA level and response to these stimuli fully recovered by 24 h of removing the drug, indicating that the beta3-AR protein and its coupling to adenylyl cyclase rapidly followed the changes in mRNA. Thus, TZDs can rapidly reduce beta3-AR expression at the transcriptional level, acting through PPAR-gamma2. The rapid turnover and responses of beta3-AR to perturbations, along with numerous other factors reported to regulate its expression, suggest a tight control of beta3-AR and function. Lastly, leptin being the only other known gene suppressed by TZDs, the present studies support a concerted lipogenic effect of these drugs.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Barz, A. Hoffmann, M. Panhuysen, and D. Spengler Peroxisome Proliferator-Activated Receptor {gamma} Is a Zac Target Gene Mediating Zac Antiproliferation Cancer Res., December 15, 2006; 66(24): 11975 - 11982. [Abstract] [Full Text] [PDF]

				H. Sell, J. P. Berger, P. Samson, G. Castriota, J. Lalonde, Y. Deshaies, and D. Richard Peroxisome Proliferator-Activated Receptor {gamma} Agonism Increases the Capacity for Sympathetically Mediated Thermogenesis in Lean and ob/ob Mice Endocrinology, August 1, 2004; 145(8): 3925 - 3934. [Abstract] [Full Text] [PDF]

				W.-C. Hsueh, S. A. Cole, A. R. Shuldiner, B. A. Beamer, J. Blangero, J. E. Hixson, J. W. MacCluer, and B. D. Mitchell Interactions Between Variants in the {beta}3-Adrenergic Receptor and Peroxisome Proliferator-Activated Receptor-{gamma}2 Genes and Obesity Diabetes Care, April 1, 2001; 24(4): 672 - 677. [Abstract] [Full Text]

				T. Yamauchi, J. Kamon, H. Waki, K. Murakami, K. Motojima, K. Komeda, T. Ide, N. Kubota, Y. Terauchi, K. Tobe, et al. The Mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) Deficiency and PPARgamma Agonist Improve Insulin Resistance J. Biol. Chem., October 26, 2001; 276(44): 41245 - 41254. [Abstract] [Full Text] [PDF]