title: Pioglitazone in adult rats reverses immediate postnatal overfeeding-induced metabolic, hormonal, and inflammatory alterations.
abstract: Immediate postnatal overfeeding in rats, obtained by reducing the litter size, results in early-onset obesity. Such experimental paradigm programs overweight, insulin resistance, dyslipidemia, increased adipose glucocorticoid metabolism [up-regulation of glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)], and overexpression of proinflammatory cytokines in mesenteric adipose tissue (MAT) in adulthood. We studied the effects of pioglitazone, a PPARγ agonist, treatment on the above-mentioned overfeeding-induced alterations. Nine-month-old rats normofed or overfed during the immediate postnatal period were given pioglitazone (3 mg/kg/day) for 6 weeks. Pioglitazone stimulated weight gain and induced a redistribution of adipose tissue toward epididymal location with enhanced plasma adiponectin. Treatment normalized postnatal overfeeding-induced metabolic alterations (increased fasting insulinemia and free fatty acids) and mesenteric overexpression of GR, 11β-HSD11, CD 68, and proinflammatory cytokines mRNAs, including plasminogen-activator inhibitor type 1. Mesenteric GR mRNA levels correlated positively with mesenteric proinflammatory cytokines mRNA concentrations. In vitro incubation of MAT obtained from overfed rats demonstrated that pioglitazone induced a down-regulation of GR gene expression and normalized glucocorticoid-induced stimulation of 11β-HSD1 and plasminogen-activator inhibitor type 1 mRNAs. Our data show for the first time that the metabolic, endocrine, and inflammatory alterations induced by early-onset postnatal obesity can be reversed by pioglitazone at the adulthood. They demonstrate that pioglitazone, in addition to its well-established effect on adipose tissue redistribution and adiponectin secretion, reverses programing-induced adipose GR, 11β-HSD1, and proinflammatory cytokines overexpression, possibly through a GR-dependent mechanism.
authors.affiliation: Aix-Marseille Univ, Faculté de Médecine, 13385, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Boullu-Ciocca
authors.affiliation: Aix-Marseille Univ, Faculté de Médecine, 13385, Marseille, France.|Inserm, UMR1062, "Nutrition, Obesity and Risk of Thrombosis", 13385, Marseille, France.|INRA, UMR1260, 13385, Marseille, France.
authors.forename: V
authors.initials: V
authors.lastname: Tassistro
authors.affiliation: Aix-Marseille Univ, Faculté de Médecine, 13385, Marseille, France.|Inserm, UMR1062, "Nutrition, Obesity and Risk of Thrombosis", 13385, Marseille, France.|INRA, UMR1260, 13385, Marseille, France.
authors.forename: A
authors.initials: A
authors.lastname: Dutour
authors.affiliation: Aix-Marseille Univ, Faculté de Médecine, 13385, Marseille, France. michel.grino@gmail.com.|Inserm, UMR1062, "Nutrition, Obesity and Risk of Thrombosis", 13385, Marseille, France. michel.grino@gmail.com.|INRA, UMR1260, 13385, Marseille, France. michel.grino@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Grino
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004353:Drug Evaluation, Preclinical; D005260:Female; D006963:Hyperphagia / Q000150:complications; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D008297:Male; D009765:Obesity / Q000209:etiology / Q000517:prevention & control*; D000077205:Pioglitazone; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D052242:Adiponectin; D007004:Hypoglycemic Agents; D017395:Plasminogen Activator Inhibitor 1; D011965:Receptors, Glucocorticoid; D045162:Thiazolidinediones; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000077205:Pioglitazone
keywords: 11β-Hydroxysteroid dehydrogenase type 1; Glucocorticoid receptor; Inflammation; Metabolic syndrome; Pioglitazone; Postnatal programing