A high fat diet modifies brain neurotransmitter profile and hippocampal proteome and morphology in an IUGR pig model

Intrauterine Growth Restriction (IUGR) is a pathological condition that hinders the correct growth of the foetus during pregnancy due to oxygen or nutrient deficiency. Consequently, the foetus adapts its metabolism and physiology to survive in such scarce environment. The major adaptation is the so called “brain sparing”; this effect gives priority to brain development to ensure the individual survival. Nevertheless, this does not warrant the normal development of the brain and the risk exists of neurological and cognitive deficits at short or long term. In turn, this adaptation leads to other systemic alterations that affect the energetic metabolism, thus inducing the emergence of a fairly characterized phenotype called “thrifty phenotype”. This phenotype is responsible for the metabolic alterations that last up until adulthood, which increase the incidence of some diseases like diabetes and metabolic syndrome. On the other hand, diets rich in fat are known to exert pernicious effects Using a pig model of IUGR, animals are classified as normal birth weight (NBW) or low birth weight (LBW). We have studied the effect of a long-term high fat diet (HFD) on the neurological alterations regarding the neurotransmitter profile in several brain areas, the morphology of the hippocampus and the proteome of this same brain area. Our hypothesis is that those animals that were affected by IUGR during their gestation, and therefore were born LBW, will present a different susceptibility to a HFD than NBW animals when they become adults. Our results indicate that HFD had a significant effect on the neurotransmitter profile of the hippocampus, amygdala, hypothalamus, striatum and prefrontal cortex. The most affected neurotransmitter was serotonin (5-HT), thus affecting the indolamine pathway. On the other hand, HFD does not provoke relevant changes in the morphology of the hippocampus. Finally, the proteomic analysis revealed that, in some instances, NBW and LBW animals respond to HFD in different ways. In particular, NBW animals present changes in the mitochondrial respiratory chain and oxidative phosphorylation, and in the extracellular matrix and its interaction with the cell. LBW animals present differences in RNA splicing, anterograde and retrograde transport and the mTOR pathway.

宫内生长受限（Intrauterine Growth Restriction, IUGR）是一种病理状态，因氧气或营养缺乏阻碍胎儿在妊娠期间的正常生长发育。胎儿会调整自身代谢与生理机能，以在这种匮乏环境中存活，其核心适应机制即为所谓的“脑 sparing效应（brain sparing）”：该效应优先保障大脑发育，以确保个体存活。然而，这一适应机制并不能保证大脑的正常发育，短期或长期均存在神经系统与认知功能缺陷的风险。此类适应还会引发其他系统性改变，影响能量代谢，进而催生特征明确的“节俭表型（thrifty phenotype）”。该表型会导致代谢改变持续至成年阶段，增加糖尿病、代谢综合征等疾病的发病风险。另一方面，高脂饮食（high fat diet, HFD）的有害影响已得到广泛证实。本研究采用IUGR猪模型，将实验动物划分为正常出生体重（normal birth weight, NBW）组与低出生体重（low birth weight, LBW）组，探究长期高脂饮食对多个脑区神经递质谱、海马体（hippocampus）形态以及该脑区蛋白质组（proteome）相关神经改变的影响。本研究的假说为：妊娠期间受IUGR影响、出生时为低出生体重的个体，在成年后相较于正常出生体重个体，对高脂饮食的易感性存在差异。研究结果显示，高脂饮食对海马体、杏仁核（amygdala）、下丘脑（hypothalamus）、纹状体（striatum）及前额叶皮层（prefrontal cortex）的神经递质谱均产生了显著影响，其中受影响最显著的神经递质为血清素（serotonin, 5-HT），进而干扰了吲哚胺通路（indolamine pathway）。此外，高脂饮食并未对海马体形态造成显著改变。最后，蛋白质组学分析表明，在部分情况下，正常出生体重与低出生体重动物对高脂饮食的响应存在差异：具体而言，正常出生体重动物的线粒体呼吸链（mitochondrial respiratory chain）与氧化磷酸化（oxidative phosphorylation）过程、细胞外基质（extracellular matrix）及其与细胞的相互作用出现了显著变化；而低出生体重动物则在RNA剪接（RNA splicing）、顺向和逆向运输（anterograde and retrograde transport）以及mTOR通路（mTOR pathway）中存在差异。