Maternal Western diet exposure increases periportal fibrosis beginning in utero in nonhuman primate offspring

Nash, Michael J.; Dobrinskikh, Evgenia; Newsom, Sean A.; Messaoudi, Ilhem; Janssen, Rachel C.; Aagaard, Kjersti M.; McCurdy, Carrie E.; Gannon, Maureen; Kievit, Paul; Friedman, Jacob E.; Wesolowski, Stephanie R.

doi:10.1172/jci.insight.154093

Cited by 13 publications

(19 citation statements)

References 80 publications

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“…In a baboon model where maternal obesity was attained, Puppala et al showed a trend toward increased hepatic lipid accumulation and more severe steatosis, assessed histologically, that did not progress toward NASH in the fetus (48). This is in contrast to our findings and those of Wesolowski et al (12) and McCurdy et al (79) in obese Japanese macaques where fetuses from WD-fed dams had higher hepatic TGs associated with impaired mitochondrial function and increased fibrogenesis, which Nash et al demonstrated was localized to the hepatic periportal region (98).…”

Section: Discussioncontrasting

confidence: 99%

Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver

Sugino

Mandala

Janssen

et al. 2022

Preprint

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Maternal consumption of a high-fat, Western-style diet (WD) disrupts the maternal/infant microbiome and contributes to developmental programming of the immune system and nonalcoholic fatty liver disease (NAFLD) in the offspring. Epigenetic changes, including non-coding miRNAs in the fetus and/or placenta may also underlie this risk. We previously showed that obese nonhuman primates (NHP) fed a WD during pregnancy results in the loss of beneficial maternal gut microbes and dysregulation of cellular metabolism and mitochondrial dysfunction in the fetal liver, leading to a perturbed postnatal immune response with accelerated NAFLD in juvenile offspring. Here, we investigated associations between WD-induced maternal metabolic and microbiome changes, in the absence of obesity, and miRNA and gene expression changes in the placenta and fetal liver. After ~8-11 months of maternal WD feeding (mWD), dams were similar in body weight but exhibited mild, systemic inflammation (elevated CRP and neutrophil count) and dyslipidemia (increased triglycerides and cholesterol) compared with dams fed a control diet. The maternal gut microbiome was mainly comprised of Lactobacillales and Clostridiales, with significantly decreased alpha diversity (P = 0.0163) in WD-fed dams but no community-wide differences (P = 0.26). At 0.9 gestation, mRNA expression of IL6 and TNF in mWD-exposed placentas trended higher, while increased triglycerides, expression of pro-inflammatory CCR2, and histological evidence for fibrosis were found in mWD-exposed fetal livers. In the mWD-exposed fetus, hepatic expression levels of miR-204-5p and miR-145-3p were significantly downregulated, whereas in mWD-exposed placentas, miR-182-5p and miR-183-5p were significantly decreased. Notably, miR-1285-3p expression in the liver and miR-183-5p in the placenta were significantly associated with inflammation and lipid synthesis pathway genes, respectively. Blautia and Ruminococcus were significantly associated with miR-122-5p in liver, while Coriobacteriacea and Prevotellacea were strongly associated with miR-1285-3p in the placenta; both miRNAs are implicated in pathways mediating postnatal growth and obesity. Our findings demonstrate that mWD shifts the maternal microbiome, lipid metabolism, and inflammation prior to obesity and are associated with epigenetic changes in the placenta and fetal liver. These changes may underlie inflammation, oxidative stress, and fibrosis patterns that drive NAFLD and metabolic disease risk in the next generation.

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Section: Discussioncontrasting

confidence: 99%

Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver

Sugino

Mandala

Janssen

et al. 2022

Preprint

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“…Likewise, energy-dense diets reduce glucose tolerance, alter insulin sensitivity in late pregnancy and feto-placental glucose metabolism, as insulin/IGF signaling is impaired, leading to maternal metabolic dysfunction that can have several consequences for fetal growth ( 16 , 30 ). For example, experimental studies have disclosed that energy-dense diets promote fetal hepatic steatosis, due to an increase in circulating triglycerides, and hypoxemia, increasing amino acid metabolism for energy production in fetal liver ( 31 , 32 ). Furthermore, clinical studies disclosed that low adherence to the Mediterranean diet (characterized by the consumption of a high intake of extra virgin oil, fruits, cereals, legumes, vegetables; and a moderate/low intake of fish, seafood, eggs, meat and dairy products) is associated with an altered GH/IGF-1 response, resulting in a poor body composition and cardiometabolic profile ( 21 , 33 ).…”

Section: Energy-dense (High Intake Of Sugars and Saturated Fatty Acid...mentioning

confidence: 99%

Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?

Martín-Estal

Castorena‐Torres

2022

Front. Endocrinol.

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Gestational diabetes mellitus (GDM), is one of the most important pregnancy complications affecting approximately 15% of pregnant women. It is related to several gestational adverse outcomes in the fetus, e.g., macrosomia, shoulder dystocia, stillbirth, neonatal hypoglycemia, and respiratory distress. Women with GDM have a high risk of developing type 2 diabetes in the future. The pathogenesis of GDM is not completely understood; nevertheless, two factors could contribute to its development: β-cell dysfunction and failure in insulin secretion in response to insulin resistance induced by gestation. Both processes, together with the physiological activities of the insulin-like growth factors (IGFs), play a crucial role in glucose transport to the fetus and hence, fetal growth and development. IGFs (both IGF-1 and IGF-2) and their binding proteins (IGFBPs) regulate glucose metabolism and insulin sensitivity. Maternal nutritional status determines the health of the newborn, as it has substantial effects on fetal growth and development. Maternal obesity and an energy-dense diet can cause an increase in insulin and IGF-1 serum levels, producing metabolic disorders, such as insulin resistance, GDM, and high birth weight (> 4,000 g) due to a higher level of body fat. In this way, in GDM pregnancies there is an increase in IGF-1 and IGF-2 serum levels, and a decrease in IGFBP-1 and 4 serum levels, suggesting the crucial role of the insulin/IGF system in this gestational outcome. Here, the present review tries to elucidate the role that energy-dense diets and the insulin/IGF-1 signaling pathway perform in GDM pregnancies.

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“…Findings from studies in humans and animal models suggests that exposure to an obesogenic diet during the perinatal period increases an individual’s risk of developing adult metabolic diseases, including obesity and NAFLD, in childhood [ 11 , 12 , 14 , 34 , 35 , 36 ]. Emerging literature suggests that supplementation with antioxidants such as PQQ [ 32 ], N-acetylcysteine [ 37 ], and gut microbial products, including the short-chain FA butyrate [ 38 , 39 , 40 ], during gestation blunts the detrimental effects of maternal obesity on offspring metabolic health.…”

Section: Discussionmentioning

confidence: 99%

“…Fetal exposure to a suboptimal maternal environment, such as poor diet, excess gestational weight gain, or gestational diabetes, increases offspring risk of obesity and metabolic syndrome in humans and in animal models [ 8 , 9 ]. In mouse and nonhuman primate (NHP) models, we and others have demonstrated that fetuses of high-fat diet (HFD)-fed dams show early signs of NAFLD, i.e., elevated liver triglycerides (TGs), oxidative stress, and evidence for periportal collagen deposition and stellate cell activation [ 10 , 11 , 12 ]. This lipotoxic phenotype persisted in NHP offspring through 1 year of age, even after implementing a healthy diet postweaning [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In mouse and nonhuman primate (NHP) models, we and others have demonstrated that fetuses of high-fat diet (HFD)-fed dams show early signs of NAFLD, i.e., elevated liver triglycerides (TGs), oxidative stress, and evidence for periportal collagen deposition and stellate cell activation [ 10 , 11 , 12 ]. This lipotoxic phenotype persisted in NHP offspring through 1 year of age, even after implementing a healthy diet postweaning [ 12 ]. Moreover, switching NHP dams to a healthy diet prior to pregnancy prevented these effects in offspring liver [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Maternal Pyrroloquinoline Quinone Supplementation Improves Offspring Liver Bioactive Lipid Profiles throughout the Lifespan and Protects against the Development of Adult NAFLD

Mandala

Dobrinskikh

Janssen

et al. 2022

IJMS

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Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric nonalcoholic fatty liver disease (NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with nonalcoholic steatohepatitis (NASH), a leading etiology for liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with NAFLD begin in utero; however, safe dietary therapeutics to blunt developmental programming of NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that pyrroloquinoline quinone (PQQ), a potent dietary antioxidant, protected offspring of WD-fed dams from development of NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic lipid profiles of WD-exposed offspring, upregulating peroxisome proliferator-activated receptor (PPAR) α signaling and mitochondrial fatty acid oxidation to markedly attenuate triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic phosphatidylcholine/phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved glucose tolerance. Notably, levels of protective n − 3 polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n − 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain fatty acids and plays a unique role in modifying specific bioactive lipid species critical for protection against NAFLD risk in later life.

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Maternal Western diet exposure increases periportal fibrosis beginning in utero in nonhuman primate offspring

Cited by 13 publications

References 80 publications

Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver

Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver

Gestational Diabetes Mellitus and Energy-Dense Diet: What Is the Role of the Insulin/IGF Axis?

Maternal Pyrroloquinoline Quinone Supplementation Improves Offspring Liver Bioactive Lipid Profiles throughout the Lifespan and Protects against the Development of Adult NAFLD

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