Fetal cardiac growth is associated with in utero gut colonization.

BACKGROUND AND AIMS: Intra-uterine metabolic environment predicts newborns' cardiac morphology, metabolism and future health. In adults, gut microbiota composition relates to altered cardiac structure and metabolism. We investigated the relationship between gut microbiota colonization and fetal cardiac growth. METHODS AND RESULTS: Bacterial composition in meconium samples of 26 healthy, full-term newborns was assessed by 16S rDNA gene sequencing. Its relationship with birth echocardiographic parameters, and the interaction with cord blood levels of inflammatory markers were investigated. Correlative and cluster analysis, linear discriminant analysis effect size and predictive functional analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied. Fetal left ventricle growth was related to gut microbiota composition at birth. Specifically, left ventricle posterior wall thickness (LVPW) greater than 4 mm was associated with lower microbiota beta and alpha diversity, depletion (LDA score > 3) of several bacteria at each taxonomic level, including Lactobacillales, and enrichment (LDA score > 5) in Enterobacteriales and Enterobacteriaceae. The latter was significantly related to cord blood gamma-glutamyltransferase levels (r = 0.58, p = 0.0057). Functionally, a thicker LVPW was related to up-regulation of pathways involved in lipopolysaccharide biosynthesis (+50%, p = 0.045 in correlative analysis) and energy metabolism (+12%, p = 0.028), and down-regulation of pathways involved in xenobiotic biodegradation (-21 to -53%, p = 0.0063-0.039), PPAR signaling (-24%, p = 0.021) and cardiac muscle contraction (-100%, p = 0.049). CONCLUSION: Fetal cardiac growth and gut colonization are associated. Greater neonatal LVPW thickness is related to lower diversity of the gut microbiota community, depletion of bacteria having anti-remodeling effects, and enrichment in bacteria functionally linked to inflammation.

The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle.

BACKGROUND AND AIMS: Metabolic factors initiating adipose tissue expansion and ectopic triglyceride accumulation are not completely understood. We aimed to investigate the independent role of circulating glucose, NEFA and insulin on glucose and NEFA uptake, and lipogenesis in skeletal muscle and subcutaneous adipose tissue (SCAT). METHODS AND RESULTS: Twenty-two pigs were stratified according to four protocols: 1) and 2) low NEFA + high insulin ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia), 3) high NEFA + low insulin (fasting), 4) low NEFA + low insulin (nicotinic acid). Positron emission tomography with [18F]fluoro-2-deoxyglucose and [11C]acetate, was combined with [14C]acetate and [U-13C]palmitate enrichment techniques to assess glucose and lipid metabolism. Hyperinsulinaemia increased glucose extraction, whilst hyperglycaemia enhanced glucose uptake in skeletal muscle and SCAT. In SCAT, during hyperglycaemia, elevated glucose uptake was accompanied by greater [U-13C]palmitate-TG enrichment compared to the other groups, and by a 39% increase in de novo lipogenesis (DNL) compared to baseline, consistent with a 70% increment in plasma lipogenic index. Conversely, in skeletal muscle, [U-13C]palmitate-TG enrichment was higher after prolonged fasting. CONCLUSIONS: Our data show the necessary role of hyperglycaemia-hyperinsulinaemia vs euglycaemia-hyperinsulinaemia in promoting expansion of TG stores in SCAT, by the consensual elevation in plasma NEFA and glucose uptake and DNL. In contrast, skeletal muscle NEFA uptake for TG synthesis is primarily driven by circulating NEFA levels. These results suggest that a) prolonged fasting or dietary regimens enhancing lipolysis might promote muscle steatosis, and b) the control of glucose levels, in association with adequate energy balance, might contribute to weight loss.

Elevated Glucose Oxidation, Reduced Insulin Secretion, and a Fatty Heart May Be Protective Adaptions in Ischemic CAD.

BACKGROUND: Insulin resistance, ß-cell dysfunction, and ectopic fat deposition have been implicated in the pathogenesis of coronary artery disease (CAD) and type 2 diabetes, which is common in CAD patients. We investigated whether CAD is an independent predictor of these metabolic abnormalities and whether this interaction is influenced by superimposed myocardial ischemia. METHODS AND RESULTS: We studied CAD patients with (n = 8) and without (n = 14) myocardial ischemia and eight non-CAD controls. Insulin sensitivity and secretion and substrate oxidation were measured during fasting and oral glucose tolerance testing. We used magnetic resonance imaging/spectroscopy, positron emission and computerized tomography to characterize CAD, cardiac function, pericardial and abdominal adipose tissue, and myocardial, liver, and pancreatic triglyceride contents. Ischemic CAD was characterized by elevated oxidative glucose metabolism and a proportional decline in ß-cell insulin secretion and reduction in lipid oxidation. Cardiac function was preserved in CAD groups, whereas cardiac fat depots were elevated in ischemic CAD compared to non-CAD subjects. Liver and pancreatic fat contents were similar in all groups and related with surrounding adipose masses or systemic insulin sensitivity. CONCLUSIONS: In ischemic CAD patients, glucose oxidation is enhanced and correlates inversely with insulin secretion. This can be seen as a mechanism to prevent glucose lowering because glucose is required in oxygen-deprived tissues. On the other hand, the accumulation of cardiac triglycerides may be a physiological adaptation to the limited fatty acid oxidative capacity. Our results underscore the urgent need of clinical trials that define the optimal/safest glycemic range in situations of myocardial ischemia.

Maternal adiposity and infancy growth predict later telomere length: a longitudinal cohort study.

BACKGROUND/OBJECTIVES: Maternal overweight and obesity during pregnancy, and childhood growth patterns are risk factors influencing long-term health outcomes among the offspring. Furthermore, poor health condition has been associated with shorter leukocyte telomere length in adult subjects. We aimed to assess whether maternal adiposity during pregnancy and growth trajectory during infancy predict leukocyte telomere length (LTL) in later life. SUBJECTS/METHODS: We studied a cohort of 1082 subjects belonging to the Helsinki Birth Cohort Study, born between 1934 and 1944. They underwent two clinical visits 10 years apart (2001-2004 and 2011-2013), during which LTL and anthropometrics were assessed. Birth records included birth weight, length, maternal body mass index (BMI) at the end of pregnancy. Serial measurements of height and weight from birth to 11 years were available. RESULTS: Higher maternal BMI was associated with shorter LTL in elderly women (r=-0.102, P=0.024) but not in men. Also, in women but not in men shorter LTL and greater telomere shortening over a 10-year interval were predicted by higher weight at 12 months of age (P=0.008 and P=0.029, respectively), and higher weight gain during the first 12 months of life (P=0.008 and P=0.006, respectively), particularly between 6 and 9 months of age (P=0.002 for both LTL and LTL shortening rate). A correlation between younger age at adiposity rebound and shorter LTL at 60 years (P=0.022) was also found. CONCLUSIONS: High maternal adiposity during pregnancy is associated with shorter LTL in elderly female offspring, but not in men. Moreover, higher weight and weight gain during the first year of life and younger age at adiposity rebound predict shorter LTL in older age in women, suggesting that rapid growth during the perinatal period accelerates cellular aging in late adulthood.

Endothelin system mRNA variation in the heart of Zucker rats: evaluation of a possible balance with natriuretic peptides.

BACKGROUND AND AIMS: The deregulation of neurohormonal systems, including the natriuretic peptide (NP) and endothelin (ET) systems, may increase the possibility of developing obesity-related risk. The aim of our paper was to evaluate ET system mRNA variation in heart of the Zucker rat model together with the simultaneous evaluation of the NP system transcriptomic profile. In order to analyze the link between the ET-1 system and the inflammatory process, the cardiac expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α was also measured. METHODS AND RESULTS: Zucker rats of 11-13 weeks were subdivided into obese rats (O, n = 20) and controls (CO, n = 20): half of them were studied under fasting conditions (CO(fc)-O(fc)) and the remainder after the induction of acute hyperglycemia (CO(AH)-O(AH)). Cardiac mRNA expression of TNF-α, IL-6, and NP/ET-1 systems was evaluated by Real-Time polymerase chain reaction. No significant difference for pre-proET-1, ET-A, and ET-B mRNA expression was detected between O and CO, whereas significantly lower mRNA levels of the ECE-1 were observed in O (p = 0.02). Regarding NPs, only BNP mRNA expression decreased significantly in O with respect to CO (p = 0.01). A down-regulation of NPR-B and NPR-C and an up-regulation of NPR-A were observed in O. No significant difference for IL-6 and TNF-α mRNA was revealed. Subdividing into fasting and hyperglycemic rats, many of the genes studied maintained their mRNA expression pattern almost unchanged. CONCLUSIONS: The modulation of ET-1/NP systems in obesity could be a useful starting point for future studies aimed at identifying new therapeutic strategies for the treatment of cardiometabolic syndrome.

Imaging of Organ Metabolism in Obesity and Diabetes: Treatment Perspectives.

Obesity and diabetes are growing threats for cardiovascular diseases (CVD) and heart failure. In order to identify early and effective treatment or prevention targets, it is fundamental to dissect the role of each organ and the sequence of events leading from health to obesity, diabetes and cardiovascular diseases. The advancements in imaging modalities to evaluate organ-specific metabolism in humans in vivo is substantially contributing to the stratification of risk, identification of organ-specific culprits and development of targeted treatment strategies. This review summarizes the contribution provided by imaging of the heart, skeletal muscle, adipose tissue, liver, pancreas, gut and brain to the understanding of the pathogenesis and cardio-metabolic complications of obesity and diabetes, and to the monitoring of treatment responses in humans. We conclude by suggesting emerging fields of investigation, including the role of cardiac fat in the pathogenesis of cardiovascular disease, the conversion of white into brown adipose tissue in the treatment of obesity, the control of weight and energy balance by the brain, the integration between omics and imaging technologies to help establish biomarkers, and the characterization of gut metabolism in relation with the gut microbiome, opening a very promising preventive/therapeutic perspective.

The interaction of blood flow, insulin, and bradykinin in regulating glucose uptake in lower-body adipose tissue in lean and obese subjects.

CONTEXT: Impaired adipose tissue (AT) blood flow has been implicated in the pathogenesis of insulin resistance in obesity. Insulin and bradykinin are meal-stimulated promoters of AT blood flow and glucose metabolism. OBJECTIVE: We tested whether blood flow regulates glucose metabolism in AT, insulin and bradykinin exert additive effects on AT blood flow and metabolism, and any of these actions explains the insulin resistance observed in obese individuals. DESIGN: Perfusion and glucose metabolism in the AT of the thighs were studied by positron emission tomography and H(2)(15)O (flow tracer) and (18)F-2-fluoro-2-deoxyglucose. Study I included five subjects in whom positron emission tomography imaging was performed in the fasting state during intraarterial infusion of bradykinin in the left leg; the right leg served as a control. Study II included seven lean and eight obese subjects in whom the imaging protocol was performed during euglycemic hyperinsulinemia. RESULTS: Bradykinin alone doubled fasting AT blood flow without modifying glucose uptake. Hyperinsulinemia increased AT blood flow (P ≤ 0.05) similarly in lean and obese individuals. In the lean group, bradykinin increased insulin-mediated AT glucose uptake from 8.6 ± 1.6 to 12.3 ± 2.4 µmol/min · kg (P = 0.038). In the obese group, AT glucose uptake was impaired (5.0 ± 1.0 µmol/min · kg, P = 0.05 vs. the lean group), and bradykinin did not exert any metabolic action (6.0 ± 0.8 µmol/min · kg, P = 0.01 vs. the lean group). CONCLUSION: AT blood flow is not an independent regulator of AT glucose metabolism. Insulin is a potent stimulator of AT blood flow, and bradykinin potentiates the hemodynamic and metabolic actions of insulin in lean but not in obese individuals.

A low shear stress modular bioreactor for connected cell culture under high flow rates.

A generic "system on a plate" modular multicompartmental bioreactor array which enables microwell protocols to be transferred directly to the bioreactor modules, without redesign of cell culture experiments or protocols is described. The modular bioreactors are simple to assemble and use and can be easily compared with standard controls since cell numbers and medium volumes are quite similar. Starting from fluid dynamic and mass transport considerations, a modular bioreactor chamber was first modeled and then fabricated using "milli-molding," a technique adapted from soft lithography. After confirming that the shear stress was extremely low in the system in the range of useful flow rates, the bioreactor chambers were tested using hepatocytes. The results show that the bioreactor chambers can increase or maintain cell viability and function when the flow rates are below 500 microL/min, corresponding to wall shear stresses of 10(-5) Pa or less at the cell culture surface.

Performance management: an essential program for poison centers.

Medico-legal liability and cost effectiveness mandate that poison information specialist performance be optimal. To maximize performance we developed and implemented a performance management program to achieve the objectives of high quality assurance in a cost-effective environment. The program can objectively assess, monitor, develop, discipline and financially compensate poison center staff. The performance standards, jointly developed by the staff and management, are the cornerstone of the program. They serve as a means of measuring and quantifying poison information specialist performance based upon compliance with responsibilities outlined in the standards. Our program enables the poison information specialist to optimize performance and also be cognizant of suboptimal work. Each staff person works with management to develop personal goals, objectives, and a plan for professional growth. Performance standards facilitate good management by improving communication, providing objective feedback, making orientation consistent, and providing an objective basis for promotion and compensation. They also provide an objective basis for dismissing unsatisfactory employees when performance is consistently suboptimal. Since personnel salaries account for 80% of a poison center's budget, effective performance management is essential.