title: Intrauterine growth restriction alters term fetal baboon hypothalamic appetitive peptide balance.
abstract: Neurons controlling appetite are located in the hypothalamic arcuate nuclei (ARH). Offspring appetite regulation has been shown to be modified by dysregulation of ARH nuclear development. Most ARH developmental studies have been in altricial rodents whose hypothalamic development is predominantly postnatal. In primates including humans, much development of hypothalamic appetite regulatory centers occurs before birth. We hypothesized that i) appetitive peptides are abundantly expressed by 90 percent gestation (0.9G), ready for postnatal function; ii) by 0.9G, intrauterine growth restriction (IUGR) increases the orexigenic:anorexigenic peptide ratio; iii) IUGR increases fetal glucocorticoid receptor (GR) expression; and iv) IUGR decreases STAT3, which signals inhibition of appetite. We developed a fetal baboon IUGR model resulting from reduced maternal nutrition. Pregnant baboons were fed ad libitum, controls (CTR; n=24), or 70% CTR diet to produce IUGR (n=14). C-section was performed at 0.9G. In CTR (n=7) and IUGR (n=6) fetal brains, ARH appetite regulatory peptides (neuropeptide Y (NPY) and proopiomelanocortin (POMC)) were quantified immunohistochemically. Fetal plasma cortisol was raised in IUGR fetuses. We observed that NPY and POMC were well expressed by 0.9G. IUGR increased NPY, GR, and active phosphorylated GR and decreased POMC and phosphorylated form of STAT3. We conclude that IUGR dysregulates ARH development in ways that will reset the appetitive neuropeptide balance in favor of increased appetite drive in postnatal life. We postulate that changes in peptide abundance are in part due to increased fetal cortisol and ARH GR. These changes may contribute to predisposition to obesity in IUGR offspring.
authors.affiliation: Department of Obstetrics and Gynecology, Center for Pregnancy and Newborn Research, The University of Texas Health Science Center San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA.
authors.forename: Cun
authors.initials: C
authors.lastname: Li
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: McDonald
authors.forename: Guoyao
authors.initials: G
authors.lastname: Wu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Nijland
authors.forename: Peter W
authors.initials: PW
authors.lastname: Nathanielsz
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000502:physiology; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D039382:Maternal Nutritional Physiological Phenomena; D009478:Neuropeptide Y / Q000378:metabolism*; D010215:Papio; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D009478:Neuropeptide Y; D011965:Receptors, Glucocorticoid; D050796:STAT3 Transcription Factor; D011333:Pro-Opiomelanocortin