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Author Milton, Flora Aparecida ♦ Cvoro, Aleksandra ♦ Amato, Angelica A. ♦ Sieglaff, Douglas H. ♦ Filgueira, Carly S. ♦ Arumanayagam, Anithachristy Sigamani ♦ Caro Alves de Lima, Maria do ♦ Rocha Pitta, Ivan ♦ Assis Rocha Neves, Francisco de ♦ Webb, Paul
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ADIPOSE TISSUE ♦ COMPARATIVE EVALUATIONS ♦ DMSO ♦ EDEMA ♦ GENES ♦ GLUCOSE ♦ HEART FAILURE ♦ INFLAMMATION ♦ INSULIN ♦ LIGANDS ♦ METABOLIC DISEASES ♦ MICE ♦ RECEPTORS ♦ SENSITIVITY ♦ SIDE EFFECTS ♦ WEIGHT
Abstract Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists that improve insulin resistance but trigger side effects such as weight gain, edema, congestive heart failure and bone loss. GQ-16 is a PPARγ partial agonist that improves glucose tolerance and insulin sensitivity in mouse models of obesity and diabetes without inducing weight gain or edema. It is not clear whether GQ-16 acts as a partial agonist at all PPARγ target genes, or whether it displays gene-selective actions. To determine how GQ-16 influences PPARγ activity on a gene by gene basis, we compared effects of rosiglitazone (Rosi) and GQ-16 in mature 3T3-L1 adipocytes using microarray and qRT-PCR. Rosi changed expression of 1156 genes in 3T3-L1, but GQ-16 only changed 89 genes. GQ-16 generally showed weak effects upon Rosi induced genes, consistent with partial agonist actions, but a subset of modestly Rosi induced and strongly repressed genes displayed disproportionately strong GQ-16 responses. PPARγ partial agonists MLR24 and SR1664 also exhibit disproportionately strong effects on transcriptional repression. We conclude that GQ-16 displays a continuum of weak partial agonist effects but efficiently represses some negatively regulated PPARγ responsive genes. Strong repressive effects could contribute to physiologic actions of GQ-16. - Highlights: • GQ-16 is an insulin sensitizing PPARγ ligand with reduced harmful side effects. • GQ-16 displays a continuum of weak partial agonist activities at PPARγ-induced genes. • GQ-16 exerts strong repressive effects at a subset of genes. • These inhibitor actions should be evaluated in models of adipose tissue inflammation.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2015-08-28
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 464
Issue Number 3


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