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Maternal obesity (MO) affects >60% of pregnancies in the US and is associated with fetal re-programming of metabolic disease susceptibility in the offspring, including nonalcoholic fatty liver disease (NAFLD). NAFLD is the most prevalent liver disease worldwide, affecting >30% of obese youth, without approved pharmacological interventions. This project is therefore significant because it addresses a critical unmet need for developing safe and effective therapeutics for MO to attenuate NAFLD risk, beginning in utero. In rodents, non-human primates (NHP) and humans, we and others have shown that MO pregnancies exhibit altered microbiome (MB) function, subclinical endotoxemia, metabolic inflammation and oxidative stress, resulting in placental inflammation and functional maladaptation (nutrient transport, blood flow). These maladaptive signals converge and epigenetically program fetal bone marrow hematopoietic stem and progenitor cells (HSPCs), monocytes and liver macrophages (Mφ) to a pro-inflammatory phenotype that contributes to programming the fetal liver (glucose, lipid control, NAFLD susceptibility). Using a novel olive baboon (Papio anubis) NHP model of Western diet induced (WD)/MO, our preliminary data show that WD/MO-exposed juvenile offspring exhibit elevated NAFLD markers by 1 year of age. Our rodent studies have shown that supplementation of WD/MO dams with the microbial nutrient and dietary antioxidant pyrroloquinoline quinone (PQQ), a bioactive compound with potent immunomodulatory activity, protects offspring from NAFLD; further, the gut MB may contribute to driving PQQ’s hepatoprotective effects. Our promising preliminary data in obese female baboons show that PQQ significantly attenuates systemic subclinical endotoxemia (LPS) and inflammation (CRP, sCD163), and improves serum cholesterol. PQQ targets mitochondrial function, oxidative stress, inflammation, and lipid metabolism, shown to be mediators of metabolic and epigenetic reprogramming in HSPCs, liver and bone marrow Mφ. However, the safety and efficacy of PQQ as a therapeutic capable of preventing programming of NAFLD in obese pregnancy have not been established in a translatable, preclinical model. This proposal aims to supplement WD/MO dams with PQQ and use state-of- the-art large scale sequencing approaches integrated with clinical biochemical measures to test the following hypothesis: PQQ during WD/MO pregnancy Aim 1) improves maternal gut MB function and relieves maternal metabolic inflammation, Aim 2) ameliorates placental maladaptation and inflammation, and Aim 3) blunts liver and bone marrow epigenetic reprogramming, mitigating emergence of a NAFLD phenotype in fetuses at 0.9 gestation. If successful, this project will open the door to understanding the molecular pathways underlying early origins of pediatric NAFLD. Our findings will be critically important for establishing next steps in the translation of PQQ as a therapeutic in MO human pregnancy and preventing transmission of NAFLD risk to the next generation.
