Nutritional Programming in the Rat Is Linked to Long-Lasting Changes in Nutrient Sensing and Energy Homeostasis in the Hypothalamus

Ricardo Orozco-Solís,Omar Guzmán-Quevedo,Sandra Lopes De Souza,Rhowena J B Matos,Rémi Houlgatte,Audrey Bihouée,Raul Manhães De Castro,Francisco Bolaños-Jiménez,Manuel Tena-Sempere

doi:10.1371/journal.pone.0013537

Abstract

BackgroundNutrient deficiency during perinatal development is associated with an increased risk to develop obesity, diabetes and hypertension in the adulthood. However, the molecular mechanisms underlying the developmental programming of the metabolic syndrome remain largely unknown.Methodology/Principal FindingsGiven the essential role of the hypothalamus in the integration of nutritional, endocrine and neuronal cues, here we have analyzed the profile of the hypothalamus transcriptome in 180 days-old rats born to dams fed either a control (200 g/kg) or a low-protein (80 g/kg) diet through pregnancy and lactation. From a total of 26 209 examined genes, 688 were up-regulated and 309 down-regulated (P<0.003) by early protein restriction. Further bioinformatic analysis of the data revealed that perinatal protein restriction permanently alters the expression of two gene clusters regulating common cellular processes. The first one includes several gate keeper genes regulating insulin signaling and nutrient sensing. The second cluster encompasses a functional network of nuclear receptors and co-regulators of transcription involved in the detection and use of lipid nutrients as fuel which, in addition, link temporal and nutritional cues to metabolism through their tight interaction with the circadian clock.Conclusions/SignificanceCollectively, these results indicate that the programming of the hypothalamic circuits regulating energy homeostasis is a key step in the development of obesity associated with malnutrition in early life and provide a valuable resource for further investigating the role of the hypothalamus in the programming of the metabolic syndrome.

Highlights

In the past two decades, there has been an important increase in the incidence of the metabolic syndrome worldwide
Phenotypic characteristics of LP rats At birth, the offspring born to dams fed the low protein diet weighed significantly less than their control counterparts (5.9760.09 g vs 7.0060.18; P,0.0001) but they showed later a delayed catch-up growth such that at the completion of the study no statistically significant differences in body weight were observed between the two groups (Table 1)
The functional categories associated with cellular signaling pathways, and transcription processes were over-represented in the up-regulated group, whereas the functional categories related to metabolism and cell cycle were over-represented in the down regulated group

Summary

Introduction

In the past two decades, there has been an important increase in the incidence of the metabolic syndrome worldwide. Infants born small for gestational age, as a result of a deficient provision of macro- and micronutrients during development, are at increased risk of developing obesity, insulin resistance, cardiovascular diseases and hypertension during adulthood [2]. To explain these observations, it has been hypothesised that the nutritional environment during the critical period of perinatal development programs whole body energy homeostasis for optimal survival under nutritionallydeficient conditions. The molecular mechanisms underlying the developmental programming of the metabolic syndrome remain largely unknown

Methods

Results

Conclusion