title: Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Regulates the Hypothalamo-Pituitary-Thyroid (HPT) Axis via Type 2 Deiodinase in Male Mice.
abstract: The hypothalamic activation of thyroid hormones by type 2 deiodinase (D2), catalyzing the conversion of thyroxine to T3, is critical for the proper function of the hypothalamo-pituitary-thyroid (HPT) axis. Regulation of D2 expression in tanycytes alters the activity of the HPT axis. However, signals that regulate D2 expression in tanycytes are poorly understood. The pituitary adenylate cyclase-activating polypeptide (PACAP) increases intracellular cAMP level, a second messenger known to stimulate the DIO2 gene; however, its importance in tanycytes is not completely characterized. Therefore, we tested whether this ubiquitously expressed neuropeptide regulates the HPT axis through stimulation of D2 in tanycytes. PACAP increased the activity of human DIO2 promoter in luciferase reporter assay that was abolished by mutation of cAMP-response element. Furthermore, PAC1R receptor immunoreactivity was identified in hypothalamic tanycytes, suggesting that these D2-expressing cells could be regulated by PACAP. Intracerebroventricular PACAP administration resulted in increased D2 activity in the mediobasal hypothalamus, suppressed Trh expression in the hypothalamic paraventricular nucleus, and decreased Tshb expression in the pituitary demonstrating that PACAP affects the D2-mediated control of the HPT axis. To understand the role of endogenous PACAP in the regulation of HPT axis, the effect of decreased PACAP expression was studied in heterozygous Adcyap1 (PACAP) knockout mice. These animals were hypothyroid that may be the consequence of altered hypothalamic T3 degradation during set-point formation of the HPT axis. In conclusion, PACAP is an endogenous regulator of the HPT axis by affecting T3-mediated negative feedback via cAMP-induced D2 expression of tanycytes.
authors.affiliation: Department of Endocrine Neurobiology (P.E., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; János Szentágothai PhD School of Neurosciences (P.E.), Semmelweis University, Budapest H-1085, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Department of Gene Technology and Developmental Neurobiology (Á.D.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Anatomy (D.R., B.D.F.), University of Pécs Medical School, Pécs H-7624, Hungary; and Laboratory of Molecular Neuropharmacology (H.H.) and iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology (H.H.), Graduate School of Pharmaceutical Sciences, Osaka University, and Molecular Research Center for Children's Mental Development H.H.), United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: P
authors.initials: P
authors.lastname: Egri
authors.affiliation: Department of Endocrine Neurobiology (P.E., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; János Szentágothai PhD School of Neurosciences (P.E.), Semmelweis University, Budapest H-1085, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Department of Gene Technology and Developmental Neurobiology (Á.D.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Anatomy (D.R., B.D.F.), University of Pécs Medical School, Pécs H-7624, Hungary; and Laboratory of Molecular Neuropharmacology (H.H.) and iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology (H.H.), Graduate School of Pharmaceutical Sciences, Osaka University, and Molecular Research Center for Children's Mental Development H.H.), United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Fekete
authors.affiliation: Department of Endocrine Neurobiology (P.E., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; János Szentágothai PhD School of Neurosciences (P.E.), Semmelweis University, Budapest H-1085, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Department of Gene Technology and Developmental Neurobiology (Á.D.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Anatomy (D.R., B.D.F.), University of Pécs Medical School, Pécs H-7624, Hungary; and Laboratory of Molecular Neuropharmacology (H.H.) and iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology (H.H.), Graduate School of Pharmaceutical Sciences, Osaka University, and Molecular Research Center for Children's Mental Development H.H.), United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: Á
authors.initials: Á
authors.lastname: Dénes
authors.affiliation: Department of Endocrine Neurobiology (P.E., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; János Szentágothai PhD School of Neurosciences (P.E.), Semmelweis University, Budapest H-1085, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Department of Gene Technology and Developmental Neurobiology (Á.D.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Anatomy (D.R., B.D.F.), University of Pécs Medical School, Pécs H-7624, Hungary; and Laboratory of Molecular Neuropharmacology (H.H.) and iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology (H.H.), Graduate School of Pharmaceutical Sciences, Osaka University, and Molecular Research Center for Children's Mental Development H.H.), United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Reglődi
authors.affiliation: Department of Endocrine Neurobiology (P.E., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; János Szentágothai PhD School of Neurosciences (P.E.), Semmelweis University, Budapest H-1085, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Department of Gene Technology and Developmental Neurobiology (Á.D.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Anatomy (D.R., B.D.F.), University of Pécs Medical School, Pécs H-7624, Hungary; and Laboratory of Molecular Neuropharmacology (H.H.) and iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology (H.H.), Graduate School of Pharmaceutical Sciences, Osaka University, and Molecular Research Center for Children's Mental Development H.H.), United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Endocrine Neurobiology (P.E., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; János Szentágothai PhD School of Neurosciences (P.E.), Semmelweis University, Budapest H-1085, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Department of Gene Technology and Developmental Neurobiology (Á.D.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Anatomy (D.R., B.D.F.), University of Pécs Medical School, Pécs H-7624, Hungary; and Laboratory of Molecular Neuropharmacology (H.H.) and iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology (H.H.), Graduate School of Pharmaceutical Sciences, Osaka University, and Molecular Research Center for Children's Mental Development H.H.), United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: B D
authors.initials: BD
authors.lastname: Fülöp
authors.affiliation: Department of Endocrine Neurobiology (P.E., C.F., B.G.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; János Szentágothai PhD School of Neurosciences (P.E.), Semmelweis University, Budapest H-1085, Hungary; Department of Medicine (C.F.), Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts 02111; Department of Gene Technology and Developmental Neurobiology (Á.D.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1083, Hungary; Department of Anatomy (D.R., B.D.F.), University of Pécs Medical School, Pécs H-7624, Hungary; and Laboratory of Molecular Neuropharmacology (H.H.) and iPS Cell-Based Research Project on Brain Neuropharmacology and Toxicology (H.H.), Graduate School of Pharmaceutical Sciences, Osaka University, and Molecular Research Center for Children's Mental Development H.H.), United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Suita, Osaka 565-0871, Japan.
authors.forename: Balázs
authors.initials: B
authors.lastname: Gereben
mesh_terms: D000818:Animals; D015153:Blotting, Western; D057809:HEK293 Cells; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007150:Immunohistochemistry; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects* / Q000378:metabolism*; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013963:Thyroid Hormones; D013972:Thyrotropin; D000097564:Iodothyronine Deiodinase Type II