Maternal Perinatal Undernutrition Drastically Reduces Postnatal Leptin Surge and Affects the Development of Arcuate Nucleus Proopiomelanocortin Neurons in Neonatal Male Rat Pups

Abstract

A growing body of evidence suggests that maternal undernutrition sensitizes the offspring to the development of energy balance metabolic disorders such as type 2 diabetes, dyslipidemia, and obesity. The present study aimed at examining the impact of maternal undernutrition on leptin plasma levels in newborn male rats and on the arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that are major leptin targets. Using a model of perinatal maternal 50% food-restricted diet (FR50) in the rat, we evaluated leptin plasma levels and hypothalamic POMC and NPY gene expression from postnatal day (PND) 4 to PND30 in both control and FR50 offspring. In control rats, a postnatal peak of plasma leptin was observed between PND4 and PND14 that reached a maximal value at PND10 (5.17 ؎ 0.53 ng/ml), whereas it was dramatically reduced in FR50 pups with the higher concentration at PND7 (0.93 ؎ 0.23 ng/ml). In FR50 animals, using semiquantitative RT-PCR and in situ hybridization, we showed that the hypothalamic POMC mRNA level was decreased from PND14 until PND30, whereas NPY gene expression was not significantly modified. In PND21 FR50 animals, we observed strikingly reduced immunoreactive ␤-endorphin nerve fibers projecting to the hypothalamic paraventricular nucleus without affecting NPY projections. Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups. These alterations might contribute to the adult metabolic disorders resulting from perinatal growth retardation. (Endocrinology 149: 470 -475, 2008)

Early and Long-term Undernutrition in Female Rats Exacerbates the Metabolic Risk Associated with Nutritional Rehabilitation

“…We found that the leptin surge was much shorter in the undernourished rats and did not peak at 10 days. Comparable results have been reported in other models of early nutrition imbalances (32,33). These deficiencies could reflect decreased milk or leptin production, or impaired absorption.…”

Genomic imprinting as an adaptative model of developmental plasticity

“…Many imprinted genes show high expression in key components of the hypothalamo-pituitary axis (our observations; [74,85]) and although genetic mouse models of altered dosage at the Dlk1-Dio3, Peg3 and Gnas loci show altered ''set points'' of metabolic axes there is, to our knowledge, currently no data linking changes in the early life environment with changes in the central nervous system expression of imprinted genes [86][87][88][89].…”

The hypothalamus–adipose axis is a key target of developmental programming by maternal nutritional manipulation

“…Thirdly, post-natal leptin surge was modified following maternal nutrition manipulation (i.e. suppressed, Delahaye et al (2008)). Finally, leptin activated adipogenesis by promoting differentiation of preadipocytes (Bol et al 2009) whereas it showed antilipogenic effects on mature adipocytes (Huan et al 2003).…”