Dynamic glucose disposal is driven by reduced endogenous glucose production in response to voluntary wheel running: A stable isotope approach

© 2020 the American Physiological Society. Dynamic glucose disposal is driven by reduced endogenous glucose production in response to voluntary wheel running: A stable isotope approach. Am J Physiol Endocrinol Metab 319: E2-E10, 2020. First published April 28, 2020; doi:10.1152/ajpendo.00450.2019.-To resolve both the systems level and molecular mechanisms responsible for exerciseinduced improvements in glucose tolerance, we sought to test the effect of voluntary wheel running exercise on postprandial glucose dynamics. We utilized a stable isotope-labeled oral glucose tolerance test (SI-OGTT) incorporating complementary deuterium glucose tracers at a 1:1 ratio (2-2H-glucose and 6-6 2H-glucose; 2g/kg lean body mass) to distinguish between endogenous glucose production (EGP) and whole-body glucose disposal. SI-OGTT was performed in C57BL/6J mice after 8 wk on a high-fat diet (HFD; 45% fat). Mice were then randomized to either a wheel-running cage (n = 13, HFD Ex) or a normal cage (n = 13, HFD Sed) while maintaining the HFD for 4 wk before performing a SI-OGTT. HFD Ex mice demonstrated improvements in whole blood glucose total area under the curve (AUC) that was attributed primarily to a reduction in EGP AUC. Serum insulin levels measured at 0 and 15 min post-glucose gavage were significantly elevated in the HFD Sed mice, whereas HFD Ex mice demonstrated the expected reduction in insulin at both time points. Overall, exercise improved hepatic insulin sensitivity by reducing postprandial EGP, but also increased whole-body glucose disposal. Finally, these results demonstrate the benefits of exercise on hepatic insulin sensitivity by combining a more physiological route of glucose administration (oral glucose) with the resolution of stable isotope tracers. These novel observations clearly demonstrate that SI-OGTT is a sensitive and cost-effective method to measure exercise adaptations in obese mice with as little as 2 μl of tail blood

Tumor Progression Locus 2 (Tpl2) Deficiency Does Not Protect against Obesity-Induced Metabolic Disease

Obesity is associated with a state of chronic low grade inflammation that plays an important role in the development of insulin resistance. Tumor progression locus 2 (Tpl2) is a serine/threonine mitogen activated protein kinase kinase kinase (MAP3K) involved in regulating responses to specific inflammatory stimuli. Here we have used mice lacking Tpl2 to examine its role in obesity-associated insulin resistance. Wild type (wt) and tpl2−/− mice accumulated comparable amounts of fat and lean mass when fed either a standard chow diet or two different high fat (HF) diets containing either 42% or 59% of energy content derived from fat. No differences in glucose tolerance were observed between wt and tpl2−/− mice on any of these diets. Insulin tolerance was similar on both standard chow and 42% HF diets, but was slightly impaired in tpl2−/− mice fed the 59% HFD. While gene expression markers of macrophage recruitment and inflammation were increased in the white adipose tissue of HF fed mice compared with standard chow fed mice, no differences were observed between wt and tpl2−/− mice. Finally, a HF diet did not increase Tpl2 expression nor did it activate Extracellular Signal-Regulated Kinase 1/2 (ERK1/2), the MAPK downstream of Tpl2. These findings argue that Tpl2 does not play a non-redundant role in obesity-associated metabolic dysfunction

Ultrafine particles and PM2.5 in the air of cities around the world : Are they representative of each other?

Can mitigating only particle mass, as the existing air quality measures do, ultimately lead to reduction in ultrafine particles (UFP)? The aim of this study was to provide a broader urban perspective on the relationship between UFP, measured in terms of particle number concentration (PNC) and PM2.5 (mass concentration of particles with aerodynamic diameter 1 for roadside sites and <1 for urban background sites with lower values for more polluted cities. The Pearson's r ranged from 0.09 to 0.64 for the log-transformed data, indicating generally poor linear correlation between PNC and PM2.5. Therefore, PNC and PM2.5 measurements are not representative of each other; and regulating PM2.5 does little to reduce PNC. This highlights the need to establish regulatory approaches and control measures to address the impacts of elevated UFP concentrations, especially in urban areas, considering their potential health risks.Peer reviewe

Plasma sphingosine-1-phosphate is elevated in obesity

Background: Dysfunctional lipid metabolism is a hallmark of obesity and insulin resistance and a risk factor for various cardiovascular and metabolic complications. In addition to the well known increase in plasma triglycerides and free fatty acids, recent work in humans and rodents has shown that obesity is associated with elevations in the bioactive class of sphingolipids known as ceramides. However, in obesity little is known about the plasma concentrations of sphinogsine-1-phosphate (S1P), the breakdown product of ceramide, which is an important signaling molecule in mammalian biology. Therefore, the purpose of this study was to examine the impact of obesity on circulating S1P concentration and its relationship with markers of glucose metabolism and insulin sensitivity. Methodology/Principal Findings: Plasma S1P levels were determined in high-fat diet (HFD)-induced and genetically obese (ob/ob) mice along with obese humans. Circulating S1P was elevated in both obese mouse models and in obese humans compared with lean healthy controls. Furthermore, in humans, plasma S1P positively correlated with total body fat percentage, body mass index (BMI), waist circumference, fasting insulin, HOMA-IR, HbA1c (%), total and LDL cholesterol. In addition, fasting increased plasma S1P levels in lean healthy mice. Conclusion: We show that elevations in plasma S1P are a feature of both human and rodent obesity and correlate with metabolic abnormalities such as adiposity and insulin resistance

UNICORN Babies: Understanding Circulating and Cerebral Creatine Levels of the Preterm Infant. An Observational Study Protocol

Creatine is an essential metabolite for brain function, with a fundamental role in cellular (ATP) energy homeostasis. It is hypothesized that preterm infants will become creatine deplete in the early postnatal period, due to premature delivery from a maternal source of creatine and a limited supply of creatine in newborn nutrition. This potential alteration to brain metabolism may contribute to, or compound, poor neurological outcomes in this high-risk population. Understanding Creatine for Neurological Health in Babies (UNICORN) is an observational study of circulating and cerebral creatine levels in preterm infants. We will recruit preterm infants at gestational ages 23+0–26+6, 27+0–29+6, 30+0–32+6, 33+0–36+6, and a term reference group at 39+0–40+6 weeks of gestation, with 20 infants in each gestational age group. At birth, a maternal capillary blood sample, as well as a venous cord blood sample, will be collected. For preterm infants, serial infant plasma (heel prick), urine, and nutrition samples [total parenteral nutrition (TPN), breast milk, or formula] will be collected between birth and term “due date.” Key fetomaternal information, including demographics, smoking status, and maternal diet, will also be collected. At term corrected postnatal age (CPA), each infant will undergo an MRI/1H-MRS scan to evaluate brain structure and measure cerebral creatine content. A general movements assessment (GMA) will also be conducted. At 3 months of CPA, infants will undergo a second GMA as well as further neurodevelopmental evaluation using the Developmental Assessment of Young Children – Second Edition (DAYC-2) assessment tool. The primary outcome measures for this study are cerebral creatine content at CPA and plasma and urine creatine and guanidinoacetate (creatine precursor) concentrations in the early postnatal period. We will also determine associations between (1) creatine levels at term CPA and neurodevelopmental outcomes (MRI, GMA, and DAY-C); (2) dietary creatine intake and circulating and cerebral creatine content; and (3) creatine levels and maternal characteristics. Novel approaches are needed to try and improve preterm-associated brain injury. Inclusion of creatine in preterm nutrition may better support ex utero brain development through improved cerebral cellular energy availability during a period of significant brain growth and development.Ethics Ref: HDEC 18/CEN/7 New Zealand.ACTRN: ACTRN12618000871246

Consensus-Phenotype Integration of Transcriptomic and Metabolomic Data Implies a Role for Metabolism in the Chemosensitivity of Tumour Cells

Using transcriptomic and metabolomic measurements from the NCI60 cell line panel, together with a novel approach to integration of molecular profile data, we show that the biochemical pathways associated with tumour cell chemosensitivity to platinum-based drugs are highly coincident, i.e. they describe a consensus phenotype. Direct integration of metabolome and transcriptome data at the point of pathway analysis improved the detection of consensus pathways by 76%, and revealed associations between platinum sensitivity and several metabolic pathways that were not visible from transcriptome analysis alone. These pathways included the TCA cycle and pyruvate metabolism, lipoprotein uptake and nucleotide synthesis by both salvage and de novo pathways. Extending the approach across a wide panel of chemotherapeutics, we confirmed the specificity of the metabolic pathway associations to platinum sensitivity. We conclude that metabolic phenotyping could play a role in predicting response to platinum chemotherapy and that consensus-phenotype integration of molecular profiling data is a powerful and versatile tool for both biomarker discovery and for exploring the complex relationships between biological pathways and drug response

The Discovery of a Gravitationally Lensed Supernova Ia at Redshift 2.22

We present the discovery and measurements of a gravitationally lensed supernova (SN) behind the galaxy cluster MOO J1014+0038. Based on multi-band Hubble Space Telescope and Very Large Telescope (VLT) photometry of the supernova, and VLT spectroscopy of the host galaxy, we find a 97.5% probability that this SN is a SN Ia, and a 2.5% chance of a CC SN. Our typing algorithm combines the shape and color of the light curve with the expected rates of each SN type in the host galaxy. With a redshift of 2.2216, this is the highest redshift SN Ia discovered with a spectroscopic host-galaxy redshift. A further distinguishing feature is that the lensing cluster, at redshift 1.23, is the most distant to date to have an amplified SN. The SN lies in the middle of the color and light-curve shape distributions found at lower redshift, disfavoring strong evolution to z = 2.22. We estimate an amplification due to gravitational lensing of 2.8+0.6-0.5 (1.10 +- 0.23 mag)---compatible with the value estimated from the weak-lensing-derived mass and the mass-concentration relation from LambdaCDM simulations---making it the most amplified SN Ia discovered behind a galaxy cluster