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

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.

Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques

“…However, these studies are limited to the fetal interval, and it is not yet known if these or similar observations will hold true in the postnatal interval. It is notable that, unlike the fetal skeletal muscle, the liver (35,68) as well as the pancreas (41,69) are equally sensitive to both maternal WSD and maternal obesity; that is, maternal WSD, independent of maternal obesity, was sufficient to drive the metabolic reprogramming and alter cellular development in these fetal tissues.…”

Developmental origins of nonalcoholic fatty liver disease

“…However, the effect of altered appetite regulation may be limited in the first year of life in humans, when the offspring of obese mothers are more likely to experience “catch-down” growth (31). Male non-human primates (NHP) exposed to maternal high-fat diet (HFD) have reduced sympathetic innervation of the liver, an interesting finding in light of research showing that hypothalamic inflammation can impact pancreatic islet cell function via its sympathetic innervation (32,33). However, it is still unclear what effect perturbations in the developing nervous system might have on hepatic metabolism.…”

124: Genomic variants associated with resistance to high fat diet induced obesity in a primate model

“…These values, their ratios, and derived calculations (inclusive of AUC and HOMA-IR) were thereafter employed in both raw and matrix testing as described; significant associations are shown in Figures and Supplemental Figure 3 and Table S5. All testing procedures were performed in a uniform fashion on fasting dams and as previously described [20][21][22][23][24][25][26][27][28][29][30][31][32][33] . Statistical analysis.…”

“…To identify functional and potentially novel SNPs associated with sensitivity or resistance to the development of obesity with high fat diet consumption present in our well characterized Japanese macaque (Macaca fuscata) model [20][21][22][23][24][25][26][27][28][29][30][31][32][33] , we designed an exon capture array that enriches for targeted exonic segments with similarity to the array probes (Supplemental Fig. 1).…”

“…To this end, we have spent nearly a decade establishing and characterizing the effect of obesity and chronic high fat dietary exposure on adult female dams and their offspring in Macaca fuscata (Japanese macaque) [18][19][20][21] . Specifically, we have demonstrated that a high fat diet (HFD) comprised of 36% calories from fat during gestation and lactation structures the offspring's epigenome, metabolome, and intestinal microbiome 18,19,[22][23][24][25][26][27] ; these molecular and metabolic perturbations are accompanied by persistent changes in offspring behavior and impairments in critical neural circuitry despite weaning to a healthy diet 28 .…”