title: Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice.
abstract: 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, andPtgs2), were decreased in WD PQQ-fed mice, concomitant with increased expression of fatty acid oxidation genes and decreasedPpargexpression. 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.
authors.affiliation: Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; karen.jonscher@ucdenver.edu.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Jonscher
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Stewart
authors.affiliation: Beckman Laser Institute, and.
authors.forename: Alba
authors.initials: A
authors.lastname: Alfonso-Garcia
authors.affiliation: West Coast Metabolomics Center, University of California, Davis, Davis, CA USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: DeFelice
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Xiaoxin X
authors.initials: XX
authors.lastname: Wang
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado USA.
authors.forename: Margaret J R
authors.initials: MJ
authors.lastname: Heerwagen
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado USA.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Janssen
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado USA.
authors.forename: Becky A
authors.initials: BA
authors.lastname: de la Houssaye
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Wiitala
authors.affiliation: Department of Integrative Biology, University of Colorado, Denver, Denver, Colorado, USA; and.
authors.forename: Garrett
authors.initials: G
authors.lastname: Florey
authors.affiliation: Department of Integrative Biology, University of Colorado, Denver, Denver, Colorado, USA; and.
authors.forename: Raleigh L
authors.initials: RL
authors.lastname: Jonscher
authors.affiliation: Beckman Laser Institute, and.|Department of Biomedical Engineering,University of California, Irvine, Irvine, California, USA.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Potma
authors.affiliation: West Coast Metabolomics Center, University of California, Davis, Davis, CA USA.|Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.affiliation: Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado USA.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002518:Ceramides / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D019587:Dietary Supplements; D005260:Female; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D009765:Obesity / Q000150:complications* / Q000188:drug therapy / Q000209:etiology; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism; D045542:PQQ Cofactor / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000975:Antioxidants; D002518:Ceramides; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D047495:PPAR gamma; C577686:interleukin-6, mouse; D045542:PQQ Cofactor; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: CARS; PGC-1α; antioxidant; ceramide; lipidomics