title: Increased prepubertal body weight enhances leptin sensitivity in proopiomelanocortin and neuropeptide y neurons before puberty onset in female rats.
abstract: Pubertal onset may be advanced by obesity, with leptin potentially acting as a permissive factor. We hypothesized that having increased body weight (BW) prepubertally affects the ability of leptin to activate intracellular signaling pathways and modulate the expression of hypothalamic neuropeptides involved in reproduction and metabolism. Because being raised in small litters (SLs) tends to increase BW at weaning, female rats were raised in litters of 4 or large litters (LLs) of 12 pups. Leptin (3 μg/g BW) or vehicle (saline) was injected sc at postnatal day (PND) 21 and 30. Rats raised in SLs weighed more at both ages, but relative visceral and subcutaneous fat was increased only on PND21. Serum leptin levels were not different at PND21 or PND30. At PND21, key elements of intracellular leptin signaling (phosphorylated signal transducer and activator of transcription 3 and phosphorylated Akt [p-Akt]) were lower in SL than in LL rats. Leptin injection stimulated phosphorylated signal transducer and activator of transcription 3 in both groups, with a greater increase in LL, whereas p-Akt rose only in SL rats. At PND30, basal leptin signaling did not differ between LL and SL rats. Leptin activation of Akt was similar at 45 minutes, but at 2 hours p-AKT levels were higher in SL than in LL rats, as was the decrease in neuropeptide Y mRNA and increase in pro-opiomelanocortin mRNA levels. No change in the reproductive axis was found. Thus, being raised in SLs increases BW and visceral body fat content, fails to increase plasma leptin concentrations, and increases the leptin responsiveness of both neuropeptide Y and pro-opiomelanocortin cells in the prepubertal hypothalamus.
authors.affiliation: Department of Endocrinology (D.C.-G., E.F.-M., P.A.-A., V.B., J.A.C., J.A.), Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa (D.C.-G., E.F.-M., P.A.-A., V.B., J.A.C., J.A.), 3Department of Pediatrics (D.C.-G., E.F.-M., P.A.-A., J.A.), Universidad Autónoma de Madrid, E-28049 Madrid, Spain; Centros de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (D.C.-G., E.F.-M., M.A.S.-G., P.A.-A., M.T.-S., V.B., J.A.C., J.A.), Instituto de Salud Carlos III, E-28009 Madrid, Spain; and Department of Cell Biology, Physiology and Immunology (M.A.S.-G., M.T.-S.), University of Córdoba, Instituto Maimónides de Investigacion Biomédicas de Córdoba/ Hospital Universitario Reina Sofia, 14004 Córdoba, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Castro-González
authors.forename: Esther
authors.initials: E
authors.lastname: Fuente-Martín
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sánchez-Garrido
authors.forename: Pilar
authors.initials: P
authors.lastname: Argente-Arizón
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.forename: Vicente
authors.initials: V
authors.lastname: Barrios
authors.forename: Julie A
authors.initials: JA
authors.lastname: Chowen
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012741:Sexual Maturation / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D020738:Leptin; D009478:Neuropeptide Y; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D011333:Pro-Opiomelanocortin; D051057:Proto-Oncogene Proteins c-akt