title: PPARG regulates gonadotropin-releasing hormone signaling in LbetaT2 cells in vitro and pituitary gonadotroph function in vivo in mice.
abstract: Peroxisome proliferators-activated receptor gamma (PPARG) ligands improve insulin sensitivity in type 2 diabetes and polycystic ovarian syndrome (PCOS). Despite clinical studies showing normalization of pituitary responsiveness to gonadotropin-releasing hormone (GnRH) in patients with PCOS, the precise role of PPARG in regulating the hypothalamic-pituitary-gonadal axis remains unclear. In the present study, we tested the hypothesis that the PPARG agonist rosiglitazone has a direct effect on the pituitary. In mouse LbetaT2 immortalized gonadotrophs, rosiglitazone treatment inhibited GnRH stimulation of the stress kinases p38MAPK and MAPKs/JNKs, but did not alter activation of ERKs, both in the presence and absence of activin. Furthermore, p38MAPK signaling was critical for both Lhb and Fshb promoter activity, and rosiglitazone suppressed the GnRH-mediated induction of Lhb and Fshb mRNA. Depletion of PPARG using a lentivirally encoded short hairpin RNA abolishes the effect of rosiglitazone to suppress activation of JNKs and induction of the transcription factors EGR1 and FOS as well as the gonadotropin genes Lhb and Fshb. Lastly, we show conditional knockout of Pparg in pituitary gonadotrophs caused an increase in luteinizing hormone levels in female mice, a decrease in follicle-stimulating hormone in male mice, and a fertility defect characterized by reduced litter size. Taken together, our data support a direct role for PPARG in modulating pituitary function in vitro and in vivo.
authors.affiliation: Medical Research Service, VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Sharma
authors.forename: Prem M
authors.initials: PM
authors.lastname: Sharma
authors.forename: Devendra S
authors.initials: DS
authors.lastname: Mistry
authors.forename: R Jeffery
authors.initials: RJ
authors.lastname: Chang
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
authors.forename: Nicholas J G
authors.initials: NJ
authors.lastname: Webster
mesh_terms: D028341:Activins / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005260:Female; D052681:Gonadotrophs / Q000378:metabolism* / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D028341:Activins; D007987:Gonadotropin-Releasing Hormone; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases