SUMOylation of AMPK alpha 1 by PIAS4 specifically regulates mTORC1 signalling

AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate-specific manner. Here we show that SUMOylation of Z attenuates AMPK activation specifically towards mTORC1 signalling. SUMOylation is also important for rapid inactivation of AMPK, to allow prompt restoration of mTORC1 signalling. PIAS4 and its SUMO E3 ligase activity are specifically required for the AMPK alpha 1 SUMOylation and the inhibition of AMPK alpha 1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPK alpha 1a mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKa-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPK alpha 1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth.Peer reviewe

Epigenetically Mediated Pathogenic Effects of Phenanthrene on Regulatory T Cells

Phenanthrene (Phe), a polycyclic aromatic hydrocarbon (PAH), is a major constituent of urban air pollution. There have been conflicting results regarding the role of other AhR ligands 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) and 6-formylindolo [3,2-b]carbazole (FICZ) in modifying regulatory T cell populations (Treg) or T helper (Th)17 differentiation, and the effects of Phe have been understudied. We hypothesized that different chemical entities of PAH induce Treg to become either Th2 or Th17 effector T cells through epigenetic modification of FOXP3. To determine specific effects on T cell populations by phenanthrene, primary human Treg were treated with Phe, TCDD, or FICZ and assessed for function, gene expression, and phenotype. Methylation of CpG sites within the FOXP3 locus reduced FOXP3 expression, leading to impaired Treg function and conversion of Treg into a CD4+CD25lo Th2 phenotype in Phe-treated cells. Conversely, TCDD treatment led to epigenetic modification of IL-17A and conversion of Treg to Th17 T cells. These findings present a mechanism by which exposure to AhR-ligands mediates human T cell responses and begins to elucidate the relationship between environmental exposures, immune modulation, and initiation of human disease

A Case Study: Implications of Energy Density on Weight Loss

The case study, Implications of Energy Density on Weight Loss, examined the relationship between the consumption of energy dense foods such as whole fruits, whole vegetables and fiber with weight loss. The case study examined four participants from the LITEN Up study, which focused on the effects of a diet and physical activity intervention on the reduction of risk factors for metabolic syndrome in sedentary, premenopausal (21-48y), overweight (BMI 26-32kg/m2), abdominally obese (waist circumference [WC>80cm; 31.50in]), apparently healthy women. Two of the four participants were selected based on their responsiveness (≥1lb/wk weight loss) to the intervention and were referred to as responders (R1, R2), while the remaining two participants were selected for their un-responsiveness (≤0.5lb/wk weight loss) to the intervention and were referred to as non-responders (NR1, NR2). The case study concluded that weight loss occurred with an increase in intake of whole fruits, whole vegetables and fiber. It also demonstrated that decreasing the consumption of energy dense beverages is important for weight loss.A case study on the relationship between energy density and weight loss in premenopausal women.Keywords: Weight loss, Energy densit

Serum Metabolomic Markers of Protein-Rich Foods and Incident CKD: Results From the Atherosclerosis Risk in Communities Study

RATIONALE & OBJECTIVE: While urine excretion of nitrogen estimates the total protein intake, biomarkers of specific dietary protein sources have been sparsely studied. Using untargeted metabolomics, this study aimed to identify serum metabolomic markers of 6 protein-rich foods and to examine whether dietary protein-related metabolites are associated with incident chronic kidney disease (CKD). STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A total of 3,726 participants from the Atherosclerosis Risk in Communities study without CKD at baseline. EXPOSURES: Dietary intake of 6 protein-rich foods (fish, nuts, legumes, red and processed meat, eggs, and poultry), serum metabolites. OUTCOMES: Incident CKD (estimated glomerular filtration rate \u3c 60 mL/min/1.73 m ANALYTICAL APPROACH: Multivariable linear regression models estimated cross-sectional associations between protein-rich foods and serum metabolites. C statistics assessed the ability of the metabolites to improve the discrimination of highest versus lower 3 quartiles of intake of protein-rich foods beyond covariates (demographics, clinical factors, health behaviors, and the intake of nonprotein food groups). Cox regression models identified prospective associations between protein-related metabolites and incident CKD. RESULTS: Thirty significant associations were identified between protein-rich foods and serum metabolites (fish, n = 8; nuts, n = 5; legumes, n = 0; red and processed meat, n = 5; eggs, n = 3; and poultry, n = 9). Metabolites collectively and significantly improved the discrimination of high intake of protein-rich foods compared with covariates alone (difference in C statistics = 0.033, 0.051, 0.003, 0.024, and 0.025 for fish, nuts, red and processed meat, eggs, and poultry-related metabolites, respectively; LIMITATIONS: Residual confounding and sample-storage duration. CONCLUSIONS: We identified candidate biomarkers of fish, nuts, red and processed meat, eggs, and poultry. A fish-related metabolite, 1-docosahexaenoylglycerophosphocholine (22:6n3), was associated with a lower risk of CKD

WAVE Project: Sport Nutrition Education Resources

The WAVE~Ripples for Change: Obesity Prevention in Active Youth (WAVE) project’s primary objective is to prevent unhealthy weight gain among high school athletes through healthy eating and reduced sedentary time. Educators are familiar with the myriad of challenges in presenting nutrition, diet, and physical activity information to high school students. WAVE uses adolescent athletes’ interest in sport to draw them into the topic of sport nutrition and healthy eating; helping them apply the knowledge and skills they learned in class, on the field, and in their lives. WAVE developed and field-tested an after-school program for high school athletes that includes 7 sport nutrition lessons (30 to 45 minutes each) and 3 team-building, family and consumer sciences life-skill workshops. WAVE also developed a cloud-based data management system to support the tracking of learner profiles, survey administration, big data visualization, and automated health report generation

Active Listening for Spatial Orientation in a Complex Auditory Scene

To successfully negotiate a complex environment, an animal must control the timing of motor behaviors in coordination with dynamic sensory information. Here, we report on adaptive temporal control of vocal–motor behavior in an echolocating bat, Eptesicus fuscus, as it captured tethered insects close to background vegetation. Recordings of the bat's sonar vocalizations were synchronized with high-speed video images that were used to reconstruct the bat's three-dimensional flight path and the positions of target and vegetation. When the bat encountered the difficult task of taking insects as close as 10–20 cm from the vegetation, its behavior changed significantly from that under open room conditions. Its success rate decreased by about 50%, its time to initiate interception increased by a factor of ten, and its high repetition rate “terminal buzz” decreased in duration by a factor of three. Under all conditions, the bat produced prominent sonar “strobe groups,” clusters of echolocation pulses with stable intervals. In the final stages of insect capture, the bat produced strobe groups at a higher incidence when the insect was positioned near clutter. Strobe groups occurred at all phases of the wingbeat (and inferred respiration) cycle, challenging the hypothesis of strict synchronization between respiration and sound production in echolocating bats. The results of this study provide a clear demonstration of temporal vocal–motor control that directly impacts the signals used for perception

Metabolomic analysis of insulin resistance across different mouse strains and diets

Insulin resistance is a major risk factor for many diseases. However, its underlying mechanism remains unclear in part because it is triggered by a complex relationship between multiple factors, including genes and the environment. Here, we used metabolomics combined with computational methods to identify factors that classified insulin resistance across individual mice derived from three different mouse strains fed two different diets. Three inbred ILSXISS strains were fed high-fat or chow diets and subjected to metabolic phenotyping and metabolomics analysis of skeletal muscle. There was significant metabolic heterogeneity between strains, diets, and individual animals. Distinct metabolites were changed with insulin resistance, diet, and between strains. Computational analysis revealed 113 metabolites that were correlated with metabolic phenotypes. Using these 113 metabolites, combined with machine learning to segregate mice based on insulin sensitivity, we identified C22:1-CoA, C2-carnitine, and C16-ceramide as the best classifiers. Strikingly, when these three metabolites were combined into one signature, they classified mice based on insulin sensitivity more accurately than each metabolite on its own or other published metabolic signatures. Furthermore, C22:1-CoA was 2.3-fold higher in insulin-resistant mice and correlated significantly with insulin resistance. We have identified a metabolomic signature composed of three functionally unrelated metabolites that accurately predicts whole-body insulin sensitivity across three mouse strains. These data indicate the power of simultaneous analysis of individual, genetic, and environmental variance in mice for identifying novel factors that accurately predict metabolic phenotypes like whole-body insulin sensitivity

The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner

Despite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC-specific transcription factor, SOX7, plays a crucial role in a non-cell-autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7-dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signaling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.Peer reviewe

Whole-Genome Sequencing analysis of Human Metabolome in Multi-Ethnic Populations

Circulating metabolite levels may reflect the state of the human organism in health and disease, however, the genetic architecture of metabolites is not fully understood. We have performed a whole-genome sequencing association analysis of both common and rare variants in up to 11,840 multi-ethnic participants from five studies with up to 1666 circulating metabolites. We have discovered 1985 novel variant-metabolite associations, and validated 761 locus-metabolite associations reported previously. Seventy-nine novel variant-metabolite associations have been replicated, including three genetic loci located on the X chromosome that have demonstrated its involvement in metabolic regulation. Gene-based analysis have provided further support for seven metabolite-replicated loci pairs and their biologically plausible genes. Among those novel replicated variant-metabolite pairs, follow-up analyses have revealed that 26 metabolites have colocalized with 21 tissues, seven metabolite-disease outcome associations have been putatively causal, and 7 metabolites might be regulated by plasma protein levels. Our results have depicted the genetic contribution to circulating metabolite levels, providing additional insights into understanding human disease