title: Effect of pre- and postnatal growth and post-weaning activity on glucose metabolism in the offspring.
abstract: Maternal caloric restriction during late gestation reduces birth weight, but whether long-term adverse metabolic outcomes of intra-uterine growth retardation (IUGR) are dependent on either accelerated postnatal growth or exposure to an obesogenic environment after weaning is not established. We induced IUGR in twin-pregnant sheep using a 40% maternal caloric restriction commencing from 110 days of gestation until term (∼147 days), compared with mothers fed to 100% of requirements. Offspring were reared either as singletons to accelerate postnatal growth or as twins to achieve standard growth. To promote an adverse phenotype in young adulthood, after weaning, offspring were reared under a low-activity obesogenic environment with the exception of a subgroup of IUGR offspring, reared as twins, maintained in a standard activity environment. We assessed glucose tolerance together with leptin and cortisol responses to feeding in young adulthood when the hypothalamus was sampled for assessment of genes regulating appetite control, energy and endocrine sensitivity. Caloric restriction reduced maternal plasma glucose, raised non-esterified fatty acids, and changed the metabolomic profile, but had no effect on insulin, leptin, or cortisol. IUGR offspring whose postnatal growth was enhanced and were obese showed insulin and leptin resistance plus raised cortisol. This was accompanied by increased hypothalamic gene expression for energy and glucocorticoid sensitivity. These long-term adaptations were reduced but not normalized in IUGR offspring whose postnatal growth was not accelerated and remained lean in a standard post-weaning environment. IUGR results in an adverse metabolic phenotype, especially when postnatal growth is enhanced and offspring progress to juvenile-onset obesity.
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Neele S
authors.initials: NS
authors.lastname: Dellschaft
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Marie-Cecile
authors.initials: MC
authors.lastname: Alexandre-Gouabau
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Gardner
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Antignac
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Duane H
authors.initials: DH
authors.lastname: Keisler
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Budge
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA michael.symonds@nottingham.ac.uk.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Symonds
authors.affiliation: Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA Early Life Research UnitAcademic Division of Child Health, Obstetrics and Gynaecology, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham NG7 2UH, UKINRA and University of NantesUMR-1280 Physiologie des Adaptations Nutritionnelles, CHU Hôtel Dieu, 44093 Nantes cedex 1, FranceSchool of Veterinary Medicine and ScienceThe University of Nottingham, Sutton Bonington Campus, Nottingham LE12 5RD, UKInstitute of Health SciencesCentre for Life-Course Epidemiology, and Biocentre Oulu, University of Oulu, Aapistie 5B, 90014 Oulu, FinlandOnirisLaboratoire d'Etude des Résidus et Contaminants dans les Aliments, LUNAM Université, USC INRA 1329, Nantes, FranceDepartment of Animal ScienceUniversity of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Sylvain P
authors.initials: SP
authors.lastname: Sebert
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism*; D048788:Growth and Development; D008098:Litter Size; D008297:Male; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000503:physiopathology; D012756:Sheep; D014886:Weaning
chemical_list: D005947:Glucose
keywords: IUGR; appetite regulation; cortisol; gene expression; insulin; leptin; metabolomics; obesity; perinatal growth