Exercise training and diet-induced weight loss increase markers of hepatic bile acid (BA) synthesis and reduce serum total BA concentrations in obese women.

Regular exercise has profound metabolic influence on the liver, but effects on bile acid (BA) metabolism are less well known. BAs are synthesized exclusively in the liver from cholesterol via the rate-limiting enzyme cholesterol 7 alpha-hydroxylase (CYP7A1). BAs contribute to the solubilization and absorption of lipids and serve as important signaling molecules, capable of systemic endocrine function. Circulating BAs increase with obesity and insulin resistance, but effects following exercise and diet-induced weight loss are unknown. To test if improvements in fitness and weight loss as a result of exercise training enhance BA metabolism, we measured serum concentrations of total BAs (conjugated and unconjugated primary and secondary BAs) in sedentary, obese, insulin-resistant women (N = 11) before (PRE) and after (POST) a ∼14-wk exercise and diet-induced weight loss intervention. BAs were measured in serum collected after an overnight fast and during an oral glucose tolerance test (OGTT). Serum fibroblast growth factor 19 (FGF19; a regulator of BA synthesis) and 7-alpha-hydroxy-cholesten-3-one (C4, a marker of CYP7A1 enzymatic activity) also were measured. Using linear mixed-model analyses and the change in V̇O2peak (mL/min/kg) as a covariate, we observed that exercise and weight loss intervention decreased total fasting serum BA by ∼30% (P = 0.001) and increased fasting serum C4 concentrations by 55% (P = 0.004). C4 was significantly correlated with serum total BAs only in the POST condition, whereas serum FGF19 was unchanged. These data indicate that a fitness and weight loss intervention modifies BA metabolism in obese women and suggest that improved metabolic health associates with higher postabsorptive (fasting) BA synthesis. Furthermore, pre- vs. postintervention patterns of serum C4 following an OGTT support the hypothesis that responsiveness of BA synthesis to postprandial inhibition is improved after exercise and weight loss.NEW & NOTEWORTHY Exercise and weight loss in previously sedentary, insulin-resistant women facilitates a significant improvement in insulin sensitivity and fitness that may be linked to changes in bile acid metabolism. Diet-induced weight loss plus exercise-induced increases in fitness promote greater postabsorptive bile acid synthesis while also sensitizing the bile acid metabolic system to feedback inhibition during a glucose challenge when glucose and insulin are elevated.

Infant Formula Feeding Increases Hepatic Cholesterol 7α Hydroxylase (CYP7A1) Expression and Fecal Bile Acid Loss in Neonatal Piglets.

Background: During the postnatal feeding period, formula-fed infants have higher cholesterol synthesis rates and lower circulating cholesterol concentrations than their breastfed counterparts. Although this disparity has been attributed to the uniformly low dietary cholesterol content of typical infant formulas, little is known of the underlying mechanisms associated with this altered cholesterol metabolism phenotype. Objective: We aimed to determine the molecular etiology of diet-associated changes in early-life cholesterol metabolism with the use of a postnatal piglet feeding model. Methods: Two-day-old male and female White-Dutch Landrace piglets were fed either sow milk (Sow group) or dairy-based (Milk group; Similac Advance powder) or soy-based (Soy group; Emfamil Prosobee Lipil powder) infant formulas until day 21. In addition to measuring serum cholesterol concentrations, hepatic and intestinal genes involved in enterohepatic circulation of cholesterol and bile acids were analyzed by real-time reverse-transcriptase polymerase chain reaction and Western blot. Bile acid concentrations were measured by liquid chromatography-mass spectrometry in serum, liver, and feces. Results: Compared with the Sow group, hepatic cholesterol 7α hydroxylase (CYP7A1) protein expression was 3-fold higher in the Milk group (P < 0.05) and expression was 10-fold higher in the Soy group compared with the Milk group (P < 0.05). Likewise, fecal bile acid concentrations were 3-fold higher in the Soy group compared with the Milk group (P < 0.05). Intestinal mRNA expression of fibroblast factor 19 (Fgf19) was reduced in the Milk and Soy groups, corresponding to 54% and 67% decreases compared with the Sow group. In the Soy group, small heterodimer protein (SHP) protein expression was 30% lower compared with the Sow group (P < 0.05). Conclusions: These results indicate that formula feeding leads to increased CYP7A1 protein expression and fecal bile acid loss in neonatal piglets, and this outcome is linked to reduced efficacy in inhibiting CYP7A1 expression through FGF19 and SHP transcriptional repression mechanisms.

Genotoxicity and gene expression analyses of liver and lung tissues of mice treated with titanium dioxide nanoparticles.

Titanium dioxide nanoparticles (TiO2 NPs) are used in paints, plastics, papers, inks, foods, toothpaste, pharmaceuticals and cosmetics. However, TiO2 NPs cause inflammation, pulmonary damage, fibrosis and lung tumours in animals and are possibly carcinogenic to humans. Although there are a large number of studies on the toxicities of TiO2 NPs, the data are inconclusive and the mechanisms underlying the toxicity are not clear. In this study, we used the Comet assay to evaluate genotoxicity and whole-genome microarray technology to analyse gene expression pattern in vivo to explore the possible mechanisms for toxicity and genotoxicity of TiO2 NPs. Mice were treated with three daily i.p. injections of 50 mg/kg 10 nm anatase TiO2 NPs and sacrificed 4 h after the last treatment. The livers and lungs were then isolated for the Comet assay and whole genome microarray analysis of gene expression. The NPs were heavily accumulated in liver and lung tissues. However, the treatment was positive for DNA strand breaks only in liver measured with the standard Comet assay, but positive for oxidative DNA adducts in both liver and lung as determined with the enzyme-modified Comet assay. The genotoxicity results suggest that DNA damage mainly resulted from oxidised nucleotides. Gene expression profiles and functional analyses revealed that exposure to TiO2 NPs triggered distinct gene expression patterns in both liver and lung tissues. The gene expression results suggest that TiO2 NPs impair DNA and cells by interrupting metabolic homeostasis in liver and by inducing oxidative stress, inflammatory responses and apoptosis in lung. These findings have broad implications when evaluating the safety of TiO2 NPs used in numerous consumer products.

Genotoxicity of TiO(2) anatase nanoparticles in B6C3F1 male mice evaluated using Pig-a and flow cytometric micronucleus assays.

In vivo micronucleus and Pig-a (phosphatidylinositol glycan, class A gene) mutation assays were conducted to evaluate the genotoxicity of 10 nm titanium dioxide anatase nanoparticles (TiO(2)-NPs) in mice. Groups of five 6-7-week-old male B6C3F1 mice were treated intravenously for three consecutive days with 0.5, 5.0, and 50 mg/kg TiO(2)-NPs for the two assays; mouse blood was sampled one day before the treatment and on Day 4, and Weeks 1, 2, 4, and 6 after the beginning of the treatment; Pig-a mutant frequencies were determined at Day -1 and Weeks 1, 2, 4 and 6, while percent micronucleated-reticulocyte (%MN-RET) frequencies were measured on Day 4 only. Additional animals were treated intravenously with three daily doses of 50 mg.kg TiO(2)-NPs for the measurement of titanium levels in bone marrow after 4, 24, and 48 h of the last treatment. The measurement indicated that the accumulation of the nanoparticles reached the peak in the tissue 4 h after the administration and the levels were maintained for a few days. No increase in either Pig-a mutant frequency of the frequency of %MN-RETs was detected, although the %RETs was reduced in the treated animals on Day 4 in a dose-dependent manner indicating cytotoxicity of TiO(2)-NPs in the bone marrow. These results suggest that although TiO(2)-NPs can reach the mouse bone marrow and are capable of inducing cytotoxicity, the nanoparticles are not genotoxic when assessed with in vivo micronucleus and Pig-a gene mutation tests.

Associations between maternal obesity and offspring gut microbiome in the first year of life.

BACKGROUND: Maternal obesity is an important determinant of offspring obesity risk, which may be mediated via changes in the infant microbiome. OBJECTIVES: We examined infant faecal microbiome, short-chain fatty acids (SCFA), and maternal human milk oligosaccharides (HMO) in mothers with overweight/obese body mass index (BMI) (OW) compared with normal weight (NW) (Clinicaltrials.gov NCT01131117). METHODS: Infant stool samples at 1, 6, and 12 months were analysed by 16S rRNA sequencing. Maternal (BODPOD) and infant (quantitative nuclear magnetic resonance [QMR]) adiposity were measured. HMOs at 2 months postpartum and faecal SCFAs at 1 month were also assessed. Statistical analyses included multivariable and mixed linear models for assessment of microbiome diversity, composition, and associations of taxonomic abundance with metabolic and anthropometric variables. RESULTS: At 1 month, offspring of women with obesity had lower abundance of SCFA-producing bacteria (including Ruminococcus and Turicibacter) and lower faecal butyric acid levels. Lachnospiraceae abundance was lower in OW group at 6 months, and infant fat mass was negatively associated with the levels of Sutterella. Gradient boosting machine models indicated that higher α-diversity and specific microbial taxa at 1 month predicted elevated adiposity at 12 months with overall accuracy of 76.5%. Associations between maternal HMO concentrations and infant bacterial taxa differed between NW and OW groups. CONCLUSIONS: Elevated maternal BMI is associated with relative depletion of butyrate-producing microbes and faecal butyrate in the early infant faecal microbiome. Overall microbial richness may aid in prediction of elevated adiposity in later infancy.

Early Infant Formula Feeding Impacts Urinary Metabolite Profile at 3 Months of Age.

There is a growing consensus that nutritional programming may persist and influence risk for several chronic diseases in adulthood. In the present study, we used urinary metabolic analysis in assessing diet effects on early-life metabolism. Urine samples from healthy three-month-old infants fed human milk (HM; n = 93), cow's milk-based infant formula [MF; n = 80], or soy protein-based infant formula (SF; n = 76) were analyzed with an untargeted metabolomics approach using GC-TOF MS. PLS-DA and ANOVA analyses were performed using MetaboAnalyst (v4.0). A total of 150 metabolites differed significantly among the feeding groups, including dietary-specific patterns of urinary metabolites of sugars, sugar alcohols, amino acids, and polyphenols. Urinary metabolites may mirror the infant's overall metabolism and serve as a noninvasive tool to examine the neonatal effects of diet on early-infant metabolism.