Oral leptin treatment in suckling rats ameliorates detrimental effects in hypothalamic structure and function caused by maternal caloric restriction during gestation

PLoS One. 2013 Nov 28;8(11):e81906. doi: 10.1371/journal.pone.0081906. eCollection 2013.

Abstract

A poor prenatal environment brings about perturbations in leptin surge and hypothalamic circuitry that program impaired ability to regulate energy homeostasis in adulthood. Here, using a rat model of moderate maternal caloric restriction during gestation, we aimed to investigate whether leptin supplementation with physiological doses throughout lactation is able to ameliorate the adverse developmental malprogramming effects exerted in offspring hypothalamus structure and function. Three groups of male and female rats were studied: the offspring of ad libitum fed dams (controls), the offspring of 20% calorie restricted dams during the first part of pregnancy (CR), and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Animals were sacrificed on postnatal day 25. Morphometric and immunohistochemical studies on arcuate (ARC) and paraventicular (PVN) nucleus were performed and hypothalamic expression levels of selected genes were determined. In CR males, leptin treatment restored, at least in part, the number of immunoreactive neuropeptide Y (NPY(+)) cells in ARC, the total number of cells in PVN, hypothalamic NPY, cocaine- and amphetamine-regulated transcript (CART) and suppressor of cytokine signalling-3 (SOCS-3) mRNA levels, and plasma leptin levels, which were decreased in CR animals. CR-Leptin males showed higher hypothalamic long-form leptin receptor (ObRb) mRNA levels, compared to control and CR animals. In CR females, leptin treatment reverted the increased number of cells in ARC and cell density in ARC and PVN, and reduced hypothalamic SOCS-3 mRNA expression to levels similar to controls. Leptin treatment also reverted the increased relative area of NPY(+) fibers in the PVN occurring in CR animals. In conclusion, leptin supplementation throughout lactation is able to revert, at least partly, most of the developmental effects on hypothalamic structure and function caused by moderate maternal caloric restriction during gestation, and hence making this metabolic malprogramming reversible to some extent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Animals, Suckling
  • Base Sequence
  • Body Weight
  • Caloric Restriction*
  • DNA Primers
  • Female
  • Hypothalamus / drug effects*
  • Hypothalamus / physiopathology
  • Leptin / administration & dosage*
  • Leptin / pharmacology
  • Male
  • Pregnancy
  • RNA, Messenger / genetics
  • Rats
  • Rats, Wistar

Substances

  • DNA Primers
  • Leptin
  • RNA, Messenger

Grants and funding

The research leading to these results was supported by the Spanish Government (grant AGL2009-11277), the European Union’s Seventh Framework Programme FP7 2007-2013 under grant agreement n. 244995 (BIOCLAIMS Project), and the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, CIBERobn. The Laboratory belongs to the Nutrigenomics-group, awarded as “Group of Excellence” of CAIB and supported by “Direcció General d’Universitats, Recerca i Transferència del Coneixement” of Regional Government (CAIB) and FEDER funds (EU Contract: n. FP6-506360). Jadwiga Konieczna is granted with a PhD fellowship entitled “beca para la formación de personal investigador, en el marco de un programa operativo cofinanciado por el Fondo Social Europeo”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.