Hassingrobbins2402

Cellular mechanisms causing insulin resistance (IR) in chronic kidney disease (CKD) are poorly understood. One potential mechanism is that CKD-induced inflammation activates the signal transducer and activator of transcription 3 (Stat3) in muscle. We uncovered increased p-Stat3 in muscles of mice with CKD or mice fed high fat diet (HFD). Activated Stat3 stimulates the expression of Fbxo40, a muscle-specific E3 ubiquitin ligase that stimulates ubiquitin conjugation leading to degradation of insulin receptor substrate 1 (IRS1). Evidence that STAT3 activates Fbxo40 includes 1) potential Stat3 binding sites in Fbxo40 promoters; 2) Stat3 binding to the Fbxo40 promoter and; 3) constitutively active Stat3 stimulating both Fbxo40 expression and its promoter activity. We found that IL-6 activates Stat3 in myotubes, increasing Fbxo40 expression with reduced IRS1 and p-Akt. Knockdown Fbxo40 using SiRNA from myotubes results in higher levels of IRS1 and p-Akt despite the presence of IL-6. We treated mice with a small-molecule inhibitor of Stat3 (TTI-101) and found improved glucose tolerance and insulin signaling in skeletal muscles of mice with CKD or fed a HFD. Finally, we uncovered improved glucose tolerance in mice with muscle-specific Stat3 KO vs. results in Stat3f/f mice in response to the HFD. Thus, Stat3 activation in muscle increases IR in mice. 1-Methyl-3-nitro-1-nitrosoguanidine Inhibition of Stat3 by TTI-101 could be developed into clinical strategies to improve muscle insulin signaling in inflammation and other catabolic diseases.Defining the host receptors and metabolic consequences of bacterial components can help explain how the microbiome influences metabolic diseases. Bacterial peptidoglycans that activate nucleotide-binding oligomerization domain-containing (NOD)1 worsen glucose control, whereas NOD2 activation improves glycemia. Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) is required for innate immunity instigated by NOD1 and NOD2. The role of RIPK2 in the divergent effects of NOD1 versus NOD2 on blood glucose was unknown. We found that whole body deletion of RIPK2 negated all effects of NOD1 or NOD2 activation on blood glucose during an acute, low level endotoxin challenge in mice. It was known that NOD1 in hematopoietic cells participates in insulin resistance and metabolic inflammation in obese mice. It was unknown if RIPK2 in hematopoietic cells is required for the glucose lowering and anti-inflammatory effects of NOD2 activation. We hypothesized that RIPK2 in non-hematopoietic cells dictated the glycemic effects of NOD2 activation. We found that whole-body deletion of RIPK2 prevented the glucose-lowering effects of repeated NOD2 activation that was evident during a glucose tolerance test (GTT) in HFD-fed wildtype (WT) mice. NOD2 activation lowered glucose during a GTT and lowered adipose tissue inflammation in mice with RIPK2 deleted in hematopoietic cells. We conclude that RIPK2 in non-hematopoietic cells mediates the glucose lowering and anti-inflammatory effects of NOD2-activating postbiotics. We propose a model where lipopolysaccharides and NOD1 ligands synergize in hematopoietic cells to promote insulin resistance, but NOD2 activation in non-hematopoietic cells promotes RIPK2-dependent immune tolerance and lowering of inflammation and insulin resistance.Fetal growth restriction (FGR) is associated with compromised growth and metabolic function throughout life. Intrauterine therapy of FGR with intra-amniotic insulin-like growth factor-1 (IGF1) enhances fetal growth and alters perinatal metabolism and growth in a sex-specific manner, but the adult effects are unknown. We investigated the effects of intra-amniotic IGF1 treatment of FGR on adult growth and body composition, adrenergic sensitivity, and glucose-insulin axis regulation. Placental embolisation-induced FGR was treated with 4 weekly doses of 360 µg intra-amniotic IGF1 (FGRI) or saline (FGRS). Offspring were raised to adulthood (18 months FGRI, n=12 females, 12 males; FGRS, n=13 females, 10 males) alongside offspring from un-embolised and untreated sheep (CON; n=12 females, 21 males). FGRI females had increased relative lean mass compared with CON but not FGRS (p less then 0.05; 70.6±8.2% vs. 61.4±8.2% vs. 67.6±8.2%), decreased abdominal adipose compared with CON and FGRS (p less then 0.05; 43.7±1.2% vs. 49.3±0.9% vs. 48.5±1.0%), increased glucose utilisation compared with FGRS but not CON (p less then 0.05; 9.6±1.0 vs. 6.0±0.9 vs. 7.6±0.9 mg·kgP-1P·minP-1P), and increased β-hydroxybutyric acidnon-esterified fatty acid ratio in response to adrenaline compared with CON and FGRS (p less then 0.05; 3.9±1.4 vs. 1.1±1.4 vs. 1.8±1.4). FGRS males were smaller and lighter compared with CON but not FGRI (p less then 0.05; 86.8±6.3 vs. 93.5±6.1 vs. 90.7±6.3 kg), with increased peak glucose concentration (10%) in response to a glucose load, but few other differences. These effects of intra-amniotic IGF1 therapy on adult body composition, glucose-insulin axis function, and adrenergic sensitivity could indicate improved metabolic regulation during young adulthood in female FGR sheep.We present a study demonstrating how random walk algorithms can be used for evolutionary image transition. We design different mutation operators based on uniform and biased random walks and study how their combination with a baseline mutation operator can lead to interesting image transition processes in terms of visual effects and artistic features. Using feature-based analysis we investigate the evolutionary image transition behaviour with respect to different features and evaluate the images constructed during the image transition process. Afterwards, we investigate how modifications of our biased random walk approaches can be used for evolutionary image painting. We introduce an evolutionary image painting approach whose underlying biased random walk can be controlled by a parameter influencing the bias of the random walk and thereby creating different artistic painting effects.The quality of solution sets generated by decomposition-based evolutionary multiobjective optimisation (EMO) algorithms depends heavily on the consistency between a given problem's Pareto front shape and the specified weights' distribution. A set of weights distributed uniformly in a simplex often lead to a set of well-distributed solutions on a Pareto front with a simplex-like shape, but may fail on other Pareto front shapes. It is an open problem on how to specify a set of appropriate weights without the information of the problem's Pareto front beforehand. In this paper, we propose an approach to adapt weights during the evolutionary process (called AdaW). AdaW progressively seeks a suitable distribution of weights for the given problem by elaborating several key parts in weight adaptation - weight generation, weight addition, weight deletion, and weight update frequency. Experimental results have shown the effectiveness of the proposed approach. AdaW works well for Pareto fronts with very different shapes 1) the simplex-like, 2) the inverted simplex-like, 3) the highly nonlinear, 4) the disconnect, 5) the degenerate, 6) the scaled, and 7) the highdimensional.