title: PPARγ partial agonist GQ-16 strongly represses a subset of genes in 3T3-L1 adipocytes.
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.
authors.affiliation: Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília, Brazil; Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Flora Aparecida
authors.initials: FA
authors.lastname: Milton
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Cvoro
authors.affiliation: Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília, Brazil.
authors.forename: Angelica A
authors.initials: AA
authors.lastname: Amato
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Sieglaff
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Carly S
authors.initials: CS
authors.lastname: Filgueira
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Anithachristy Sigamani
authors.initials: AS
authors.lastname: Arumanayagam
authors.affiliation: Laboratório de Planejamento e Síntese de Fármacos - LPSF, Universidade Federal de Pernambuco, Brazil.
authors.forename: Maria do Carmo Alves
authors.initials: Mdo C
authors.lastname: de Lima
authors.affiliation: Laboratório de Planejamento e Síntese de Fármacos - LPSF, Universidade Federal de Pernambuco, Brazil.
authors.forename: Ivan Rocha
authors.initials: IR
authors.lastname: Pitta
authors.affiliation: Faculdade de Ciências da Saúde, Laboratório de Farmacologia Molecular, Universidade de Brasília, Brazil.
authors.forename: Francisco
authors.initials: F
authors.lastname: de Assis Rocha Neves
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, USA. Electronic address: pwebb@HoustonMethodist.org.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: C576055:5-(5-bromo-2-methoxybenzylidene)-3-(4-methyl-benzyl)thiazolidine-2,4-dione; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: 3T3-L1; Gene expression; Partial agonist; Peroxisome proliferator activated receptor γ; Repression; Thiazolidinedione