A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity.

Rieusset, Jennifer; Touri, Fethi; Michalik, Liliane; Escher, Pascal; Desvergne, Béatrice; Niesor, Eric; Wahli, Walter (2002). A new selective peroxisome proliferator-activated receptor gamma antagonist with antiobesity and antidiabetic activity. Molecular endocrinology, 16(11), pp. 2628-2644. Endocrine Society 10.1210/me.2002-0036

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Peroxisome proliferator-activated receptor gamma (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 PPARgamma antagonist, the phosphonophosphate SR-202, which inhibits both TZD-stimulated recruitment of the coactivator steroid receptor coactivator-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 PPARgamma activity, either by treatment with SR-202 or by invalidation of one allele of the PPARgamma 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 TNFalpha and leptin secretion. Treatment with SR-202 also dramatically improves insulin sensitivity in the diabetic ob/ob mice. Thus, although we cannot exclude that its actions involve additional signaling mechanisms, SR-202 represents a new selective PPARgamma antagonist that is effective both in vitro and in vivo. Because it yields both antiobesity and antidiabetic effects, SR-202 may be a lead for new compounds to be used in the treatment of obesity and type 2 diabetes.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Ophthalmology

UniBE Contributor:

Escher, Pascal

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0888-8809

Publisher:

Endocrine Society

Language:

English

Submitter:

PD Dr. Pascal Escher

Date Deposited:

11 Jul 2017 07:50

Last Modified:

31 Jul 2017 08:31

Publisher DOI:

10.1210/me.2002-0036

PubMed ID:

12403851

BORIS DOI:

10.7892/boris.101757

URI:

https://boris.unibe.ch/id/eprint/101757

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