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: |
Pascal Escher |
Date Deposited: |
11 Jul 2017 07:50 |
Last Modified: |
05 Dec 2022 15:06 |
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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