Oral Leptin Treatment in Suckling Rats Ameliorates Detrimental Effects in Hypothalamic Structure and Function Caused by Maternal Caloric Restriction during Gestation

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.

The responses of hypothalamic NPY and OBRb mRNA expression to food deprivation develop during the neonatal‐prepubertal period and exhibit gender differences in rats

“…Another possibility is that the number of NPY neurons differs between males and females and that such differences cause discrepancies in NPY mRNA expression under fasted conditions. Konieczna et al counted the number of NPY‐positive neurons in the arcuate nucleus, an area of the hypothalamus containing abundant NPY‐positive neurons, in pre‐pubertal rats (Konieczna et al, 2013) and found that the female rats seemed to possess fewer NPY‐positive neurons than the males; however, they did not confirm this using statistical methods. On the other hand, in the present study under the fed conditions NPY mRNA expression did not differ between males and females, regardless of whether it was normalized to the expression level of GAPDH.…”

Early leptin intervention reverses perturbed energy balance regulating hypothalamic neuropeptides in the pre‐ and postnatal calorie‐restricted female rat offspring

“…This may explain the increased milk intake in PN14 CR L versus CR S . More recently, oral administration of leptin throughout the postnatal period after only a modest 20% restriction of calories during conception (E1‐E12 days) led to recovery of the hypothalamic structure and neuropeptides at PN25 (Konieczna et al, ). In our present study, this effect of exogenous leptin over a shorter postnatal period (PN2‐PN8) following late gestational calorie restriction (E11 to E21) on hypothalamic NPY and AgRP is mediated by enhanced post‐ObRb (Cottrell et al, ) signaling seen as increased pSTAT3 and reduced PTP1B and SOCS3 (both inhibitors of leptin signaling).…”

Hypothalamic effects of neonatal diet: reversible and only partially leptin dependent

“…Anti-NPY has also been shown to react with NPY-containing neurons in frozen rat brain sections following 4% paraformaldehyde perfusion fixation. This antibody has been used in several studies looking at the effects of diet manipulation or treatment with feeding-regulatory peptides such as orexins, leptin or ghrelin on NPY immunohistochemical expression (for example: Cheunsuang & Morris 2005, Kobelt et al 2008, Garcia et al 2010, Li et al 2012, Konieczna et al 2013, Pekala et al 2011.…”