A NEW SELECTIVE PPAR{gamma} ANTAGONIST WITH ANTI-OBESITY AND ANTI-DIABETIC ACTIVITY

doi:10.1210/me.2002-0036

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A NEW SELECTIVE PPAR ${gamma}$ ANTAGONIST WITH ANTI-OBESITY AND ANTI-DIABETIC ACTIVITY

Jennifer Rieusset¹, Fethi Touri¹, Liliane Michalik¹, Pascal Escher¹, Béatrice Desvergne¹, Eric Niesor¹, and Walter Wahli¹^*

¹ Institut de biologie animale, Université de Lausanne, Bâtiment de biologie, CH-1015 Lausanne, Switzerland. Present address : INSERM U449, Faculté de médecine R.T.H. Laennec, rue Guillaume Paradin, 69372 Lyon cedex 08. Ilex onc., rte des Fayards 243, 1290 Versoix/Geneva, Switzerland. Present address :Department of Physiology/Neurobiology, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland J. Rieusset and F. Touri contributed equally to this work.

^* To whom correspondence should be addressed. E-mail: Walter.Wahli{at}iba.unil.ch.

PPAR ${gamma}$ plays a key role in adipocyte differentiation and insulin sensitivity. Its synthetic ligands, the thiazolidinediones (TZD) are used as insulin sensitizers in the treatment of type 2 diabetes. These compounds induce both adipocyte differentiation in cell culture models and promote weight gain in rodents and humans. Here, we report on the identification of a new synthetic PPAR ${gamma}$ antagonist, the phosphonophosphate SR-202, which inhibits both TZD-stimulated recruitment of the coactivator SRC-1 and TZD-induced transcriptional activity of the receptor. In cell culture, SR-202 efficiently antagonizes hormone- and TZD-induced adipocyte differentiation. In vivo, decreasing PPAR ${gamma}$ activity, either by treatment with SR-202 or by invalidation of one allele of the PPAR ${gamma}$ gene, leads to a reduction of both high-fat diet-induced adipocyte hypertrophy and insulin resistance. These effects are accompanied by a smaller size of the adipocytes and a reduction of TNF ${alpha}$ and leptin secretion. Treatment with SR-202 also dramatically improves insulin sensitivity in the diabetic ob/ob mice. Thus, while we cannot exclude that its actions involve additional signaling mechanisms, SR202 represents a new selective PPAR ${gamma}$ antagonist which is effective both in vitro and in vivo. Because it yields both anti-obesity and anti-diabetic effects, SR-202 may be a lead for new compounds to be used in the treatment of obesity and type 2 diabetes.

Key words: SR-202 • PPAR ${gamma}$ antagonist • adipocyte • obesity • insulin resistance

NURSA Molecule Pages Link:

: Nuclear Receptors: PPARα | PPARδ | PPARγ | FXRα
: Coregulators: SRC-1
: Ligands: Pirinixic acid | Rosiglitazone

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				B. Desvergne, L. Michalik, and W. Wahli Transcriptional Regulation of Metabolism Physiol Rev, April 1, 2006; 86(2): 465 - 514. [Abstract] [Full Text] [PDF]

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				L. Yvan-Charvet, P. Even, M. Bloch-Faure, M. Guerre-Millo, N. Moustaid-Moussa, P. Ferre, and A. Quignard-Boulange Deletion of the Angiotensin Type 2 Receptor (AT2R) Reduces Adipose Cell Size and Protects From Diet-Induced Obesity and Insulin Resistance Diabetes, April 1, 2005; 54(4): 991 - 999. [Abstract] [Full Text] [PDF]

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				E. Santini, P. Fallahi, S. M. Ferrari, A. Masoni, A. Antonelli, and E. Ferrannini Effect of PPAR-{gamma} Activation and Inhibition on Glucose-Stimulated Insulin Release in INS-1e Cells Diabetes, December 1, 2004; 53(suppl_3): S79 - S83. [Abstract] [Full Text] [PDF]

A NEW SELECTIVE PPAR ANTAGONIST WITH ANTI-OBESITY AND ANTI-DIABETIC ACTIVITY

A NEW SELECTIVE PPAR ${gamma}$ ANTAGONIST WITH ANTI-OBESITY AND ANTI-DIABETIC ACTIVITY

				J. Rieusset, J. Seydoux, S. I. Anghel, P. Escher, L. Michalik, N. Soon Tan, D. Metzger, P. Chambon, W. Wahli, and B. Desvergne Altered Growth in Male Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}) Heterozygous Mice: Involvement of PPAR{gamma} in a Negative Feedback Regulation of Growth Hormone Action Mol. Endocrinol., October 1, 2004; 18(10): 2363 - 2377. [Abstract] [Full Text] [PDF]

				T. Imai, R. Takakuwa, S. Marchand, E. Dentz, J.-M. Bornert, N. Messaddeq, O. Wendling, M. Mark, B. Desvergne, W. Wahli, et al. Peroxisome proliferator-activated receptor {gamma} is required in mature white and brown adipocytes for their survival in the mouse PNAS, March 30, 2004; 101(13): 4543 - 4547. [Abstract] [Full Text] [PDF]

				C. L. Smith and B. W. O'Malley Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators Endocr. Rev., February 1, 2004; 25(1): 45 - 71. [Abstract] [Full Text] [PDF]

				H. Koutnikova, T.-A. Cock, M. Watanabe, S. M. Houten, M.-F. Champy, A. Dierich, and J. Auwerx Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR{gamma} hypomorphic mice PNAS, November 25, 2003; 100(24): 14457 - 14462. [Abstract] [Full Text] [PDF]

				J. D. Baxter, W. F. Young Jr., and P. Webb Cardiovascular Endocrinology: Introduction Endocr. Rev., June 1, 2003; 24(3): 253 - 260. [Full Text] [PDF]