title: Activation of PPAR-γ reduces HPA axis activity in diabetic rats by up-regulating PI3K expression.
abstract: Increased hypothalamus-pituitary-adrenal axis (HPA) activity in diabetes is strongly associated with several morbidities noted in patients with the disease. We previously demonstrated that hyperactivity of HPA axis under diabetic conditions is associated with up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal and down-regulation of glucocorticoid receptors (GR and MR) in pituitary. This study investigates the role of peroxisome proliferator-activated receptor (PPAR)-γ in HPA axis hyperactivity in diabetic rats. Diabetes was induced by intravenous injection of alloxan into fasted rats. The PPAR-γ agonist rosiglitazone and/or PI3K inhibitor wortmannin were administered daily for 18 consecutive days, starting 3days after diabetes induction. Plasma ACTH and corticosterone were evaluated by radioimmunoassay, while intensities of MC2R, proopiomelanocortin (POMC), GR, MR, PI3K p110α and PPAR-γ were assessed using immunohistochemistry. Rosiglitazone treatment inhibited adrenal hypertrophy and hypercorticoidism observed in diabetic rats. Rosiglitazone also significantly reversed the diabetes-induced increase in the MC2R expression in adrenal cortex. We noted that rosiglitazone reduced the number of corticotroph cells and inhibited both anterior pituitary POMC expression and plasma ACTH levels. Furthermore, rosiglitazone treatment was unable to restore the reduced expression of GR and MR in the anterior pituitary of diabetic rats. Rosiglitazone increased the number of PPAR-γ+cells and expression of PI3K p110α in both anterior pituitary and adrenal cortex of diabetic rats. In addition, wortmannin blocked the ability of rosiglitazone to restore corticotroph cell numbers, adrenal hypertrophy and plasma corticosterone levels in diabetic rats. In conclusion, our findings revealed that rosiglitazone down-regulates HPA axis hyperactivity in diabetic rats via a mechanism dependent on PI3K activation in pituitary and adrenal glands.
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil no. 4365, Manguinhos, CEP 21045-900 Rio de Janeiro, Brazil. Electronic address: rafaelctorres@hotmail.com.
authors.forename: Rafael Carvalho
authors.initials: RC
authors.lastname: Torres
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil no. 4365, Manguinhos, CEP 21045-900 Rio de Janeiro, Brazil. Electronic address: magalhaess.nathalia@gmail.com.
authors.forename: Nathalia Santos
authors.initials: NS
authors.lastname: Magalhães
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil no. 4365, Manguinhos, CEP 21045-900 Rio de Janeiro, Brazil. Electronic address: patmar@ioc.fiocruz.br.
authors.forename: Patrícia M R
authors.initials: PM
authors.lastname: E Silva
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil no. 4365, Manguinhos, CEP 21045-900 Rio de Janeiro, Brazil. Electronic address: mmartins@ioc.fiocruz.br.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Martins
authors.affiliation: Laboratório de Inflamação, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Av. Brasil no. 4365, Manguinhos, CEP 21045-900 Rio de Janeiro, Brazil. Electronic address: vfrias@ioc.fiocruz.br.
authors.forename: Vinicius F
authors.initials: VF
authors.lastname: Carvalho
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D006984:Hypertrophy; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000473:pathology; D008297:Male; D047495:PPAR gamma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D047495:PPAR gamma; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D019869:Phosphatidylinositol 3-Kinases; D003345:Corticosterone
keywords: Diabetes; Glucocorticoids; HPA axis; PI3K; PPAR-γ