Metabokines in the regulation of systemic energy metabolism

Metabolism consists of life-sustaining chemical reactions involving metabolites. Historically, metabolites were defined as the intermediates or end products of metabolism and considered to be passive participants changed by metabolic processes. However, recent research has redefined how we view metabolism. There is emerging evidence of metabolites which function to mediate cellular signalling and interorgan crosstalk, regulating local metabolism and systemic physiology. These bioactive metabolite signals have been termed metabokines. Metabokines regulate diverse energy metabolism pathways across multiple tissues, including fatty acid β-oxidation, mitochondrial oxidative phosphorylation, lipolysis, glycolysis and gluconeogenesis. There is increasing impetus to uncover novel metabokine signalling axes to better understand how these may be perturbed in metabolic diseases and determine their utility as therapeutic targets

North Atlantic ocean circulation and abrupt climate change during the last glaciation.

The most recent ice age was characterized by rapid and hemispherically asynchronous climate oscillations, whose origin remains unresolved. Variations in oceanic meridional heat transport may contribute to these repeated climate changes, which were most pronounced during marine isotope stage 3, the glacial interval 25 thousand to 60 thousand years ago. We examined climate and ocean circulation proxies throughout this interval at high resolution in a deep North Atlantic sediment core, combining the kinematic tracer protactinium/thorium (Pa/Th) with the deep water-mass tracer, epibenthic δ(13)C. These indicators suggest reduced Atlantic overturning circulation during every cool northern stadial, with the greatest reductions during episodic Hudson Strait iceberg discharges, while sharp northern warming followed reinvigorated overturning. These results provide direct evidence for the ocean's persistent, central role in abrupt glacial climate change

Linking the unfolded protein response to bioactive lipid metabolism and signalling in the cell non-autonomous extracellular communication of ER stress

The endoplasmic reticulum (ER) organelle is the key intracellular site of both protein and lipid biosynthesis. ER dysfunction, termed ER stress, can result in protein accretion within the ER and cell death; a pathophysiological process contributing to a range of metabolic diseases and cancers. ER stress leads to the activation of a protective signalling cascade termed the Unfolded Protein Response (UPR). However, chronic UPR activation can ultimately result in cellular apoptosis. Emerging evidence suggests that cells undergoing ER stress and UPR activation can release extracellular signals that can propagate UPR activation to target tissues in a cell non-autonomous signalling mechanism. Separately, studies have determined that the UPR plays a key regulatory role in the biosynthesis of bioactive signalling lipids including sphingolipids and ceramides. Here we weigh the evidence to combine these concepts and propose that during ER stress, UPR activation drives the biosynthesis of ceramide lipids, which are exported and function as cell non-autonomous signals to propagate UPR activation in target cells and tissues

The metabolome as a diagnostic for maximal aerobic capacity during exercise in type 1 diabetes

\ua9 The Author(s) 2024.Aims/hypothesis: Our aim was to characterise the in-depth metabolic response to aerobic exercise and the impact of residual pancreatic beta cell function in type 1 diabetes. We also aimed to use the metabolome to distinguish individuals with type 1 diabetes with reduced maximal aerobic capacity in exercise defined by V˙O2peak. Methods: Thirty participants with type 1 diabetes (≥3 years duration) and 30 control participants were recruited. Groups did not differ in age or sex. After quantification of peak stimulated C-peptide, participants were categorised into those with undetectable (<3 pmol/l), low (3–200 pmol/l) or high (>200 pmol/l) residual beta cell function. Maximal aerobic capacity was assessed by V˙O2peak test and did not differ between control and type 1 diabetes groups. All participants completed 45 min of incline treadmill walking (60% V˙O2peak) with venous blood taken prior to exercise, immediately post exercise and after 60 min recovery. Serum was analysed using targeted metabolomics. Metabolomic data were analysed by multivariate statistics to define the metabolic phenotype of exercise in type 1 diabetes. Receiver operating characteristic (ROC) curves were used to identify circulating metabolomic markers of maximal aerobic capacity (V˙O2peak) during exercise in health and type 1 diabetes. Results: Maximal aerobic capacity (V˙O2peak) inversely correlated with HbA1c in the type 1 diabetes group (r2=0.17, p=0.024). Higher resting serum tricarboxylic acid cycle metabolites malic acid (fold change 1.4, p=0.001) and lactate (fold change 1.22, p=1.23 710−5) differentiated people with type 1 diabetes. Higher serum acylcarnitines (AC) (AC C14:1, F value=12.25, p=0.001345; AC C12, F value=11.055, p=0.0018) were unique to the metabolic response to exercise in people with type 1 diabetes. C-peptide status differentially affected metabolic responses in serum ACs during exercise (AC C18:1, leverage 0.066; squared prediction error 3.07). The malic acid/pyruvate ratio in rested serum was diagnostic for maximal aerobic capacity (V˙O2peak) in people with type 1 diabetes (ROC curve AUC 0.867 [95% CI 0.716, 0.956]). Conclusions/interpretation: The serum metabolome distinguishes high and low maximal aerobic capacity and has diagnostic potential for facilitating personalised medicine approaches to manage aerobic exercise and fitness in type 1 diabetes. Graphical Abstract: (Figure presented.)

Composition of receptor tyrosine kinase-mediated lipid micro-domains controlled by adaptor protein interaction

Receptor tyrosine kinases (RTKs) are highly regulated, single pass transmembrane proteins, fundamental to cellular function and survival. Aberrancies in regulation lead to corruption of signal transduction and a range of pathological outcomes. Although control mechanisms associated with the receptors and their ligands are well understood, little is known with respect to the impact of lipid/lipid and lipid/protein interactions in the proximal plasma membrane environment. Given that the transmembrane regions of RTKs change in response to extracellular ligand binding, the lipid interactions have important consequences in influencing signal transduction. Fibroblast growth factor receptor 2 (FGFR2) is a highly regulated RTK, including under basal conditions. Binding of the adaptor protein, growth factor receptor-bound protein 2 (GRB2) to FGFR2 prevents full activation and recruitment of downstream signalling effector proteins in the absence of extracellular stimulation. Here we demonstrate that the FGFR2-GRB2 complex is sustained in a defined lipid environment. Dissociation of GRB2 from this complex due to ligand binding, or reduced GRB2 expression, facilitates the dispersion of FGFR2 into detergent-resistant membrane (DRM) micro-domains. This modification of the plasma membrane proximal to FGFR2 provides a further regulatory checkpoint which controls receptor degradation, recycling and recruitment of intracellular signalling proteins

Metabolomics dataset of PPAR-pan treated rat liver

This article contains mass spectrometry (MS) data investigating small molecule changes as an effect of a triple peroxisome proliferator-activated receptor (PPAR-pan) agonist GW625019 in the liver as described in the manuscript (Ament et al., 2016) [1]. Samples were measured using gas chromatography-mass spectrometry (GC–MS) for total fatty acid content, and liquid chromatography-mass spectrometry (LC–MS) to measure intact lipids, carnitines and selected aqueous metabolites and eicosanoids. Data files comprise of Excel (Microsoft, WA, USA) spreadsheets of identified metabolites and their area ratio values for total fatty acids, carnitines, aqueous metabolites, and eicosanoids where the intensity of the analytes were normalised to the intensity of the internal standard. In the case of open profiling intact lipid data, the Excel file contains area ratio values of retention time and mass to charge ratio pairs; again, the area ratio values were calculated by normalising to the intensity of the internal standard. It should be noted that several metabolic changes are potentially indirect (secondary, tertiary and ensuing changes)

Formation and Propagation of Matter Wave Soliton Trains

Attraction between atoms in a Bose-Einstein-Condensate renders the condensate unstable to collapse. Confinement in an atom trap, however, can stabilize the condensate for a limited number of atoms, as was observed with 7Li, but beyond this number, the condensate collapses. Attractive condensates constrained to one-dimensional motion are predicted to form stable solitons for which the attractive interactions exactly compensate for the wave packet dispersion. Here we report the formation or bright solitons of 7Li atoms created in a quasi-1D optical trap. The solitons are created from a stable Bose-Einstein condensate by magnetically tuning the interactions from repulsive to attractive. We observe a soliton train, containing many solitons. The solitons are set in motion by offsetting the optical potential and are observed to propagate in the potential for many oscillatory cycles without spreading. Repulsive interactions between neighboring solitons are inferred from their motion

Food Should not be Forgotten: Impacts of Combined Cash Transfer Receipt and Food Security on Child Education and Cognition in South Africa and Malawi.

Social protection can take many forms. Both cash transfers and food security may have important contributions to child cognitive development. This study examines the potential impact of combinations of cash transfers and food security status on child cognitive development and educational outcomes. Cross-sectional data for 796 HIV-affected children in the Child Community Care study were utilised for this analysis. Children and caregivers completed interview schedules comprised of standardised items on socio-demographics, household data, cash grant receipt and food security status, school achievement, and cognition. A series of logistic and linear regression models and marginal effects analyses were undertaken to explore the impacts of differing levels of social protection (none; either cash grant receipt or food secure status or, both in combination) on child educational and cognitive outcomes. Although all children lived in poverty-stricken households, 20% (157/796) of children did not live in a household in receipt of a cash grant and did not report food security; 32.4% (258/796) reported either component of social protection and, 47.9% (381/796) received both measures of social protection in combination. Compared to no social protection, being in receipt of either component of social protection was found to be significantly associated with being in the correct class for age, higher scores of non-verbal cognition, and higher working memory scores. Receiving both social protection measures in combination was found to be significantly associated with reduced educational risk scores, improved odds of being in the correct class for age, regular school attendance, missing less than a week of school in the previous two weeks, higher scores on measures of nonverbal cognition, higher working memory scores, and learning new things more easily. Educational and cognitive outcomes for children can be bolstered by social protection measures (cash grant receipt or food security). Benefits are enhanced when social protection is received in combination. Such findings support the notion of synergistic social protection responses for children living in environments impacted by high levels of HIV burden and deprivation

Finding Inspiration: Sharing Practice and Developing Authentic Multimedia Artifacts for Supervision of Undergraduate Research in Irish higher education

Supervision is a specialist academic practice that can be learnt through the experience of the practice of supervision itself. However, increasingly, supervisors can find inspiration from each other in structured, supported, collaborative professional development. This Chapter evaluates the perceived impact on faculty and student learning of sharing inspirational practices and creating multimedia artifacts which formed the assessment of an accredited postgraduate module entitled ‘Supervising Undergraduate Dissertations and Projects’ at a Technological University in Ireland. A range of themes are explored in the Chapter including the increasing demand for this form of professional development for academics; the importance of a peer learning approach for providing inspiration and sharing of practice; the design and development of multimedia artifacts for undergraduate supervision practice and the national context within which this work is situated

Inorganic Nitrate Promotes Glucose Uptake and Oxidative Catabolism in White Adipose Tissue through the XOR Catalyzed Nitric Oxide Pathway

An ageing global population combined with sedentary lifestyles and unhealthy diets has contributed to an increasing incidence of obesity and type 2 diabetes. These metabolic disorders are associated with perturbations to nitric oxide (NO) signaling and impaired glucose metabolism. Dietary inorganic nitrate, found in high concentration in green leafy vegetables, can be converted to NO in vivo and demonstrates anti-diabetic and anti-obesity properties in rodents. Alongside tissues including skeletal muscle and liver, white adipose tissue is also an important physiological site of glucose disposal. However, the distinct molecular mechanisms governing the effect of nitrate on adipose tissue glucose metabolism, and the contribution of this tissue to the glucose tolerant phenotype, remain to be determined. Using a metabolomic and stable-isotope labeling approach, combined with transcriptional analysis, we found that nitrate increases glucose uptake and oxidative catabolism in primary adipocytes and white adipose tissue of nitrate-treated rats. Mechanistically, we determine that nitrate induces these phenotypic changes in primary adipocytes through the xanthine oxidoreductase catalysed reduction of nitrate to nitric oxide and independently of Peroxisome Proliferator-Activated Receptor α. The nitrate-mediated enhancement of glucose uptake and catabolism in white adipose tissue may be a key contributor to the anti-diabetic effects of this anion