Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice.

Increasingly, evidence suggests that exposure to maternal obesity creates an inflammatory environment , exerting long-lasting postnatal signatures on the juvenile innate immune system and microbiome that may predispose offspring to development of fatty liver disease. We found that exposure to a maternal Western-style diet (WD) accelerated fibrogenesis in the liver of offspring and was associated with early recruitment of proinflammatory macrophages at 8-12 weeks and microbial dysbiosis as early as 3 weeks of age. We further demonstrated that bone marrow-derived macrophages (BMDMs) were polarized toward an inflammatory state at 8 weeks of age and that a potent antioxidant, pyrroloquinoline quinone (PQQ), reversed BMDM metabolic reprogramming from glycolytic toward oxidative metabolism by restoring trichloroacetic acid cycle function at isocitrate dehydrogenase.

Altered gene expression and metabolism in fetal umbilical cord mesenchymal stem cells correspond with differences in 5-month-old infant adiposity gain.

The intrauterine period is a critical time wherein developmental exposure can influence risk for chronic disease including childhood obesity. Using umbilical cord-derived mesenchymal stem cells (uMSC) from offspring born to normal-weight and obese mothers, we tested the hypothesis that changes in infant body composition over the first 5 months of life correspond with differences in cellular metabolism and transcriptomic profiles at birth. Higher long-chain acylcarnitine concentrations, lipid transport gene expression, and indicators of oxidative stress in uMSC-adipocytes were related to higher adiposity at 5 months of age.

Low Neonatal Plasma n-6/n-3 PUFA Ratios Regulate Offspring Adipogenic Potential and Condition Adult Obesity Resistance.

Adipose tissue expansion progresses rapidly during postnatal life, influenced by both prenatal maternal factors and postnatal developmental cues. The ratio of omega-6 (n-6) relative to n-3 polyunsaturated fatty acids (PUFAs) is believed to regulate perinatal adipogenesis, but the cellular mechanisms and long-term effects are not well understood. We lowered the fetal and postnatal n-6/n-3 PUFA ratio exposure in wild-type offspring under standard maternal dietary fat amounts to test the effects of low n-6/n-3 ratios on offspring adipogenesis and adipogenic potential.

Maternal obesity and increased neonatal adiposity correspond with altered infant mesenchymal stem cell metabolism.

Maternal obesity is a global health problem that increases offspring obesity risk. The metabolic pathways underlying early developmental programming in human infants at risk for obesity remain poorly understood, largely due to barriers in fetal/infant tissue sampling. Utilizing umbilical cord-derived mesenchymal stem cells (uMSC) from offspring of normal weight and obese mothers, we tested whether energy metabolism and gene expression differ in differentiating uMSC myocytes and adipocytes, in relation to maternal obesity exposures and/or neonatal adiposity.

Markers of Oxidative Stress in Human Milk do not Differ by Maternal BMI But are Related to Infant Growth Trajectories.

Objective Obesity in adults is associated with inflammation and oxidative stress. Whether or not this phenotype is reflected in human milk (HM) composition, or may impact infant growth remains unknown. We investigated whether HM from overweight/obese (OW/Ob) mothers exhibited higher concentrations of inflammatory cytokines and markers of oxidative stress.

Early PQQ supplementation has persistent long-term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice.

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.

Nicotinamide Promotes Adipogenesis in Umbilical Cord-Derived Mesenchymal Stem Cells and Is Associated with Neonatal Adiposity: The Healthy Start BabyBUMP Project.

The cellular mechanisms whereby excess maternal nutrition during pregnancy increases adiposity of the offspring are not well understood. However, nicotinamide (NAM), a fundamental micronutrient that is important in energy metabolism, has been shown to regulate adipogenesis through inhibition of SIRT1. Here we tested three novel hypotheses: 1) NAM increases the adipogenic response of human umbilical cord tissue-derived mesenchymal stem cells (MSCs) through a SIRT1 and PPARγ pathway; 2) lipid potentiates the NAM-enhanced adipogenic response; and 3) the adipogenic response to NAM is associated with increased percent fat mass (%FM) among neonates.

Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome.

Background: Increased maternal body mass index (BMI) is a robust risk factor for later pediatric obesity. Accumulating evidence suggests that human milk (HM) may attenuate the transfer of obesity from mother to offspring, potentially through its effects on early development of the infant microbiome.

Objectives: Our objective was to identify early differences in intestinal microbiota in a cohort of breastfeeding infants born to obese compared with normal-weight (NW) mothers.

C/EBPβ in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis.

Background And Objective: Atherosclerosis is both a chronic inflammatory disease and a lipid metabolism disorder. C/EBPβ is well documented for its role in the development of hematopoietic cells and integration of lipid metabolism. However, C/EBPβ's role in atherosclerotic progression has not been examined.

Women With Gestational Diabetes Mellitus Randomized to a Higher-Complex Carbohydrate/Low-Fat Diet Manifest Lower Adipose Tissue Insulin Resistance, Inflammation, Glucose, and Free Fatty Acids: A Pilot Study.

Objective: Diet therapy in gestational diabetes mellitus (GDM) has focused on carbohydrate restriction but is poorly substantiated. In this pilot randomized clinical trial, we challenged the conventional low-carbohydrate/higher-fat (LC/CONV) diet, hypothesizing that a higher-complex carbohydrate/lower-fat (CHOICE) diet would improve maternal insulin resistance (IR), adipose tissue (AT) lipolysis, and infant adiposity.

Research Design And Methods: At 31 weeks, 12 diet-controlled overweight/obese women with GDM were randomized to an isocaloric LC/CONV (40% carbohydrate/45% fat/15% protein; n = 6) or CHOICE (60%/25%/15%; n = 6) diet.

Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding.

Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD). Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT) cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens.

Transgenic increase in N-3/n-6 Fatty Acid ratio reduces maternal obesity-associated inflammation and limits adverse developmental programming in mice.

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.

CCAAT/enhancer-binding protein β (C/EBPβ) expression regulates dietary-induced inflammation in macrophages and adipose tissue in mice.

Strong evidence exists for a link between chronic low level inflammation and dietary-induced insulin resistance; however, little is known about the transcriptional networks involved. Here we show that high fat diet (HFD) or saturated fatty acid exposure directly activates CCAAT/enhancer-binding protein β (C/EBPβ) protein expression in liver, adipocytes, and macrophages. Global C/EBPβ deletion prevented HFD-induced inflammation and surprisingly increased mitochondrial gene expression in white adipose tissue along with brown adipose tissue markers PRDM16, CIDEa, and UCP1, consistent with a resistance to HFD-induced obesity.

Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues.

Objective: Skeletal muscle-specific LPL knockout mouse (SMLPL(-/-)) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition.

Research Design And Methods: Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL(-/-) and control mice.

PI3K activation by IGF-1 is essential for the regulation of membrane expansion at the nerve growth cone.

Exocytotic incorporation of plasmalemmal precursor vesicles (PPVs) into the cell surface is necessary for axonal outgrowth and is known to occur mainly at the nerve growth cone. We have demonstrated recently that plasmalemmal expansion is regulated at the growth cone by IGF-1, but not by BDNF, in a manner that is quasi independent of the neuron's perikaryon. To begin elucidating the signaling pathway by which exocytosis of the plasmalemmal precursor is regulated, we studied activation of the IRS/PI3K/Akt pathway in isolated growth cones and hippocampal neurons in culture stimulated with IGF-1 or BDNF.

Growth cone collapse induced by semaphorin 3A requires 12/15-lipoxygenase.

Detection of a repellent factor, such as a semaphorin (Sema), causes localized collapse of the growth cone and directs the neurite away from the repellent. Growth cone collapse results from concomitant cytoskeletal rearrangements and detachment of adhesion sites from the extracellular matrix, via mostly unknown signaling mechanisms. In cultures of dorsal root ganglion neurons, we found that Sema3A treatment stimulates the synthesis of the eicosanoid, 12(S)-hydroxyeicosatetraenoic acid (HETE), whereas Sema3A-induced growth cone collapse is prevented when 12(S)-HETE synthesis is blocked with an inhibitor of 12/15-lipoxygenase (LO).