Perinatal Exposure to a High-Fat Diet Is Associated with Reduced Hepatic Sympathetic Innervation in One-Year Old Male Japanese Macaques

Wilmon F Grant,Daniel L Marks,Stephanie R Thorn,Kevin L Grove,Jacob E Friedman,Lindsey E Nicol,Thierry Alquier

doi:10.1371/journal.pone.0048119

Abstract

Our group recently demonstrated that maternal high-fat diet (HFD) consumption is associated with non-alcoholic fatty liver disease, increased apoptosis, and changes in gluconeogenic gene expression and chromatin structure in fetal nonhuman primate (NHP) liver. However, little is known about the long-term effects that a HFD has on hepatic nervous system development in offspring, a system that plays an important role in regulating hepatic metabolism. Utilizing immunohistochemistry and Real-Time PCR, we quantified sympathetic nerve fiber density, apoptosis, inflammation, and other autonomic components in the livers of fetal and one-year old Japanese macaques chronically exposed to a HFD. We found that HFD exposure in-utero and throughout the postnatal period (HFD/HFD), when compared to animals receiving a CTR diet for the same developmental period (CTR/CTR), is associated with a 1.7 fold decrease in periportal sympathetic innervation, a 5 fold decrease in parenchymal sympathetic innervation, and a 2.5 fold increase in hepatic apoptosis in the livers of one-year old male animals. Additionally, we observed an increase in hepatic inflammation and a decrease in a key component of the cholinergic anti-inflammatory pathway in one-year old HFD/HFD offspring. Taken together, these findings reinforce the impact that continuous exposure to a HFD has in the development of long-term hepatic pathologies in offspring and highlights a potential neuroanatomical basis for hepatic metabolic dysfunction.

Highlights

Fetal and early postnatal development are critical periods when perturbations to the intrauterine environment can have lifelong effects on the structure and function of organs, tissues and body systems in the offspring through long lasting changes in the developmental program [1,2,3]
In previous work with this model, our group demonstrated that oxidative damage, hepatic steatosis, upregulation of phosphoJNK1 that was highly correlated with levels of fetal liver triglycerides, and increased hepatic apoptosis without evidence of hepatic inflammation was observed in high-fat diet (HFD) fetal livers [11,12]
We observed a significant upregulation in the expression of lymphotoxin-a (LTA, x2 = 5.1, 1 d.f., p = 0.02) across both sexes in the HFD/HFD group when compared to Control diet (CTR)/CTR (Table 1)

Summary

Introduction

Fetal and early postnatal development are critical periods when perturbations to the intrauterine environment can have lifelong effects on the structure and function of organs, tissues and body systems in the offspring through long lasting changes in the developmental program [1,2,3]. Recent work by our group has revealed in the nonhuman primate (NHP) that chronic exposure to a maternal high-fat diet (HFD) is associated with alterations in the fetal liver that include modifications of hepatic chromatin structure, alterations in gluconeogenic and circadian gene expression, increased apoptosis, elevated triglyceride content and evidence of oxidative stress and nonalcoholic fatty liver disease (NAFLD) [10,11,12,13]. Changes in central serotonergic systems and alterations in the development and expression of hypothalamic neuropeptides reported in fetal and one-year old HFD NHP offspring, have revealed an abnormal development of brain circuits critically involved in the autonomic regulation of glucose homeostasis with this model [14,15]

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Conclusion