RESUMO
Nonalcoholic fatty liver disease (NAFLD) is widespread in adults and children. Early exposure to maternal obesity or Western-style diet (WD) increases steatosis and oxidative stress in fetal liver and is associated with lifetime disease risk in the offspring. Pyrroloquinoline quinone (PQQ) is a natural antioxidant found in soil, enriched in human breast milk, and essential for development in mammals. We investigated whether a supplemental dose of PQQ, provided prenatally in a mouse model of diet-induced obesity during pregnancy, could protect obese offspring from progression of NAFLD. PQQ treatment given pre- and postnatally in WD-fed offspring had no effect on weight gain but increased metabolic flexibility while reducing body fat and liver lipids, compared with untreated obese offspring. Indices of NAFLD, including hepatic ceramide levels, oxidative stress, and expression of proinflammatory genes (Nos2, Nlrp3, Il6, and Ptgs2), were decreased in WD PQQ-fed mice, concomitant with increased expression of fatty acid oxidation genes and decreased Pparg expression. Notably, these changes persisted even after PQQ withdrawal at weaning. Our results suggest that supplementation with PQQ, particularly during pregnancy and lactation, protects offspring from WD-induced developmental programming of hepatic lipotoxicity and may help slow the advancing epidemic of NAFLD in the next generation.-Jonscher, K. R., Stewart, M. S., Alfonso-Garcia, A., DeFelice, B. C., Wang, X. X., Luo, Y., Levi, M., Heerwagen, M. J. R., Janssen, R. C., de la Houssaye, B. A., Wiitala, E., Florey, G., Jonscher, R. L., Potma, E. O., Fiehn, O. Friedman, J. E. Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice.
Assuntos
Antioxidantes/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/complicações , Cofator PQQ/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Ceramidas/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Feminino , Interleucina-6/genética , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/tratamento farmacológico , Obesidade/etiologia , Estresse Oxidativo , PPAR gama/metabolismo , Cofator PQQ/administração & dosagem , Cofator PQQ/farmacologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/etiologiaRESUMO
The incidence of pediatric nonalcoholic fatty liver disease has increased dramatically, and growing evidence indicates that the pathophysiology may be unique from the adult form, suggesting a role for early-life events. Recent radiologic techniques have now demonstrated that maternal obesity contributes to hepatic fat storage in newborn infants. In this review, we will explore how maternal obesity and a hyperlipidemic environment can initiate liver histopathogenesis in utero, including steatosis, mitochondrial dysfunction, oxidative stress, and inflammatory priming. Thus, early exposure to excess lipids may represent the "first hit" for the fetal liver, placing it on a trajectory toward future metabolic disease.
Assuntos
Fígado Gorduroso/embriologia , Hiperlipidemias , Fígado/embriologia , Obesidade , Complicações na Gravidez , Criança , Feminino , Humanos , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-NatalAssuntos
Exantema/diagnóstico , Tinha/diagnóstico , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido PrematuroAssuntos
Anormalidades Múltiplas/diagnóstico por imagem , Colo/anormalidades , Atresia Intestinal/diagnóstico por imagem , Intestino Delgado/anormalidades , Bexiga Urinária/anormalidades , Colo/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Recém-Nascido , Intestino Delgado/diagnóstico por imagem , Masculino , Síndrome do Abdome em Ameixa Seca/diagnóstico , Radiografia , Síndrome , Bexiga Urinária/diagnóstico por imagemRESUMO
Maternal and pediatric obesity has risen dramatically over recent years, and is a known predictor of adverse long-term metabolic outcomes in offspring. However, which particular aspects of obese pregnancy promote such outcomes is less clear. While maternal obesity increases both maternal and placental inflammation, it is still unknown whether this is a dominant mechanism in fetal metabolic programming. In this study, we utilized the Fat-1 transgenic mouse to test whether increasing the maternal n-3/n-6 tissue fatty acid ratio could reduce the consequences of maternal obesity-associated inflammation and thereby mitigate downstream developmental programming. Eight-week-old WT or hemizygous Fat-1 C57BL/6J female mice were placed on a high-fat diet (HFD) or control diet (CD) for 8 weeks prior to mating with WT chow-fed males. Only WT offspring from Fat-1 mothers were analyzed. WT-HFD mothers demonstrated increased markers of infiltrating adipose tissue macrophages (P<0.02), and a striking increase in 12 serum pro-inflammatory cytokines (P<0.05), while Fat1-HFD mothers remained similar to WT-CD mothers, despite equal weight gain. E18.5 Fetuses from WT-HFD mothers had larger placentas (P<0.02), as well as increased placenta and fetal liver TG deposition (P<0.01 and P<0.02, respectively) and increased placental LPL TG-hydrolase activity (P<0.02), which correlated with degree of maternal insulin resistance (râ=â0.59, P<0.02). The placentas and fetal livers from Fat1-HFD mothers were protected from this excess placental growth and fetal-placental lipid deposition. Importantly, maternal protection from excess inflammation corresponded with improved metabolic outcomes in adult WT offspring. While the offspring from WT-HFD mothers weaned onto CD demonstrated increased weight gain (P<0.05), body and liver fat (P<0.05 and P<0.001, respectively), and whole body insulin resistance (P<0.05), these were prevented in WT offspring from Fat1-HFD mothers. Our results suggest that reducing excess maternal inflammation may be a promising target for preventing adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.