title: Des-Acyl Ghrelin and Ghrelin O-Acyltransferase Regulate Hypothalamic-Pituitary-Adrenal Axis Activation and Anxiety in Response to Acute Stress.
abstract: Ghrelin exists in two forms in circulation, acyl ghrelin and des-acyl ghrelin, both of which have distinct and fundamental roles in a variety of physiological functions. Despite this fact, a large proportion of papers simply measure and refer to plasma ghrelin without specifying the acylation status. It is therefore critical to assess and state the acylation status of plasma ghrelin in all studies. In this study we tested the effect of des-acyl ghrelin administration on the hypothalamic-pituitary-adrenal axis and on anxiety-like behavior of mice lacking endogenous ghrelin and in ghrelin-O-acyltransferase (GOAT) knockout (KO) mice that have no endogenous acyl ghrelin and high endogenous des-acyl ghrelin. Our results show des-acyl ghrelin produces an anxiogenic effect under nonstressed conditions, but this switches to an anxiolytic effect under stress. Des-acyl ghrelin influences plasma corticosterone under both nonstressed and stressed conditions, although c-fos activation in the paraventricular nucleus of the hypothalamus is not different. By contrast, GOAT KO are anxious under both nonstressed and stressed conditions, although this is not due to corticosterone release from the adrenals but rather from impaired feedback actions in the paraventricular nucleus of the hypothalamus, as assessed by c-fos activation. These results reveal des-acyl ghrelin treatment and GOAT deletion have differential effects on the hypothalamic-pituitary-adrenal axis and anxiety-like behavior, suggesting that anxiety-like behavior in GOAT KO mice is not due to high plasma des-acyl ghrelin.
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Romana
authors.initials: R
authors.lastname: Stark
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Vanessa V
authors.initials: VV
authors.lastname: Santos
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Bram
authors.initials: B
authors.lastname: Geenen
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Agustina
authors.initials: A
authors.lastname: Cabral
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Tara
authors.initials: T
authors.lastname: Dinan
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Bayliss
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Lockie
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Alex
authors.initials: A
authors.lastname: Reichenbach
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Moyra B
authors.initials: MB
authors.lastname: Lemus
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Mario
authors.initials: M
authors.lastname: Perello
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Spencer
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kozicz
authors.affiliation: Monash Biomedicine Discovery Institute and Department of Physiology (R.S., V.V.S., J.A.B., S.H.L., A.R., M.B.L., Z.B.A.), Monash University, Clayton, Australia Monash University, Clayton, Melbourne, Victoria 3800, Australia; Department of Anatomy (B.G.M T.K.), Radboud University Medical Center, 6500HB Nijmegen, The Netherlands; Laboratory of Neurophysiology (A.C., M.P.) Multidisciplinary Institute of Cell Biology (Argentine Research Council [CONICET] and Scientific Research Commission, Province of Buenos Aires [CIC-PBA]), La Plata, Buenos Aires, Argentina; School of Health and Biomedical Sciences (T.D., S.J.S.), RMIT University, Melbourne, Victoria 3083, Australia; and Hayward Genetics Center (T.K.), Tulane University, New Orleans, Louisiana 70112.
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
mesh_terms: D000215:Acylation; D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000503:physiopathology* / Q000523:psychology; D005260:Female; D054439:Ghrelin / Q000502:physiology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000502:physiology*
chemical_list: D054439:Ghrelin; D008565:Membrane Proteins; C422650:ghrelin, des-n-octanoyl; D000217:Acyltransferases; C526983:Mboat4 protein, mouse