title: Fetal PGC-1α overexpression programs adult pancreatic β-cell dysfunction.
abstract: Adult β-cell dysfunction, a hallmark of type 2 diabetes, can be programmed by adverse fetal environment. We have shown that fetal glucocorticoids (GCs) participate in this programming through inhibition of β-cell development. Here we have investigated the molecular mechanisms underlying this regulation. We showed that GCs stimulate the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a coregulator of the GCs receptor (GR), and that the overexpression of PGC-1α represses genes important for β-cell development and function. More precisely, PGC-1α inhibited the expression of the key β-cell transcription factor pancreatic duodenal homeobox 1 (Pdx1). This repression required the GR and was mediated through binding of a GR/PGC-1α complex to the Pdx1 promoter. To explore PGC-1α function, we generated mice with inducible β-cell PGC-1α overexpression. Mice overexpressing PGC-1α exhibited at adult age impaired glucose tolerance associated with reduced insulin secretion, decreased β-cell mass, and β-cell hypotrophy. Interestingly, PGC-1α expression in fetal life only was sufficient to impair adult β-cell function whereas β-cell PGC-1α overexpression from adult age had no consequence on β-cell function. Altogether, our results demonstrate that the GR and PGC-1α participate in the fetal programming of adult β-cell function through inhibition of Pdx1 expression.
authors.affiliation: INSERM, UMRS 872, Cordeliers Research Center, Paris, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Valtat
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Riveline
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Amrit
authors.initials: A
authors.lastname: Singh-Estivalet
authors.forename: Mathieu
authors.initials: M
authors.lastname: Armanet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Venteclef
authors.forename: Adrien
authors.initials: A
authors.lastname: Besseiche
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.forename: François
authors.initials: F
authors.lastname: Tronche
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bréant
authors.forename: Bertrand
authors.initials: B
authors.lastname: Blondeau
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002478:Cells, Cultured; D005260:Female; D005508:Food Deprivation; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C084010:pancreatic and duodenal homeobox 1 protein; D005947:Glucose