TCPTP-deficiency in muscle does not alter insulin signalling and glucose homeostasis.

Aims/Hypothesis: Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The IR can serve as a substrate for the protein tyrosine phosphatases (PTP) 1B and TCPTP, which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the IR in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates IR signalling and gluconeogenesis in the liver. In this study we have assessed for the first time the role of TCPTP in the regulation of IR signalling in muscle. Methods: We generated muscle-specific TCPTP-deficient (MCK-Cre;Ptpn2lox/lox) mice and assessed the impact on glucose homeostasis and muscle IR signalling in chow versus high fat fed mice. Results: Blood glucose and insulin levels, insulin and glucose tolerances and insulininduced muscle IR activation and downstream PI3K/Akt signalling remained unaltered in chow fe

Cameriere’s European formula for age estimation: A study on the children in Bosnia and Herzegovina

Introduction: A method for age estimation, based on measurements of projections of open apices and heights of developing permanentteeth on orthopantomograms (OPTs), was presented by Cameriere in 2006 and adopted European formula was presented in 2007. Aim: This cross-sectional study tested the accuracy of Cameriere’s European formula on a sample from the City of Sarajevo, Bosniaand Herzegovina. Materials and methods: A final sample of 560 OPTs of 305 girls and 255 boys aged 8 to 14 years was obtained. The sample was collected at the Department of Orthodontics, School of Dental Medicine at the University of Sarajevo (SFUNSA). Dental age was compared to chronological age and mean absolute error (MAE) was calculated. Intra-rater and inter-rater agreement of the evaluated variables were calculated. Results: The dental age was underestimated when compared to chronological age, precisely, mean underestimation was -0.14 years ingirls and -0.17 years in boys. The values of MAE were 0.62 years in girls and 0.56 years in boys. The greatest error was found for the 14-year old group; DA was -1.04 years and -0.70 years in girls and boys respectively. Conclusion: Our results showed that Cameriere’s European formula might be a useful tool for age estimation in children from Bosnia and Herzegovina under the age of 14 years

Skeletal muscle ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise

During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl‐CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC isoforms regulate malonyl‐CoA production, an allosteric inhibitor of carnitine palmitoyltransferase 1 (CPT‐1); the primary enzyme controlling fatty acyl‐CoA flux into mitochondria for oxidation. AMP‐activated protein kinase (AMPK) is a sensor of cellular energy status that is activated during exercise or by pharmacological agents such as metformin and AICAR. In resting muscle the activation of AMPK with AICAR leads to increased phosphorylation of ACC (S79 on ACC1 and S221 on ACC2), which reduces ACC activity and malonyl‐CoA; effects associated with increased fatty acid oxidation. However, whether this pathway is vital for regulating skeletal muscle fatty acid oxidation during conditions of increased metabolic flux such as exercise/muscle contractions remains unknown. To examine this we characterized mice lacking AMPK phosphorylation sites on ACC2 (S212 in mice/S221 in humans‐ACC2‐knock‐in [ACC2‐KI]) or both ACC1 (S79) and ACC2 (S212) (ACC double knock‐in [ACCD‐KI]) during submaximal treadmill exercise and/or ex vivo muscle contractions. We find that surprisingly, ACC2‐KI mice had normal exercise capacity and whole‐body fatty acid oxidation during treadmill running despite elevated muscle ACC2 activity and malonyl‐CoA. Similar results were observed in ACCD‐KI mice. Fatty acid oxidation was also maintained in muscles from ACC2‐KI mice contracted ex vivo. These findings indicate that pathways independent of ACC phosphorylation are important for regulating skeletal muscle fatty acid oxidation during exercise/muscle contractions

T-Cell Protein Tyrosine Phosphatase Attenuates STAT3 and Insulin Signaling in the Liver to Regulate Gluconeogenesis

OBJECTIVE: Insulin-induced phosphatidylinositol 3-kinase (PI3K)/Akt signaling and interleukin-6 (IL-6)-instigated JAK/STAT3-signaling pathways in the liver inhibit the expression of gluconeogenic genes to decrease hepatic glucose output. The insulin receptor (IR) and JAK1 tyrosine kinases and STAT3 can serve as direct substrates for the T-cell protein tyrosine phosphatase (TCPTP). Homozygous TCPTP-deficiency results in perinatal lethality prohibiting any informative assessment of TCPTP's role in glucose homeostasis. Here we have used Ptpn2+/- mice to investigate TCPTP's function in glucose homeostasis. RESEARCH DESIGN AND METHODS: We analyzed insulin sensitivity and gluconeogenesis in chow versus high-fat-fed (HFF) Ptpn2+/- and Ptpn2+/+ mice and insulin and IL-6 signaling and gluconeogenic gene expression in Ptpn2+/- and Ptpn2+/+ hepatocytes. RESULTS: HFF Ptpn2+/- mice exhibited lower fasted blood glucose and decreased hepatic glucose output as determined in hyperinsulinemic euglycemic clamps and by the decreased blood glucose levels in pyruvate tolerance tests. The reduced hepatic glucose output coincided with decreased expression of the gluconeogenic genes G6pc and Pck1 and enhanced hepatic STAT3 phosphorylation and PI3K/Akt signaling in the fasted state. Insulin-induced IR-beta-subunit Y1162/Y1163 phosphorylation and PI3K/Akt signaling and IL-6-induced STAT3 phosphorylation were also enhanced in isolated Ptpn2+/- hepatocytes. The increased insulin and IL-6 signaling resulted in enhanced suppression of G6pc and Pck1 mRNA. CONCLUSIONS: Liver TCPTP antagonises both insulin and STAT3 signaling pathways to regulate gluconeogenic gene expression and hepatic glucose output

Ghrelin-AMPK Signaling Mediates the Neuroprotective Effects of Calorie Restriction in Parkinson's Disease

Jacqeline Bayliss, Romana Stark, Moyra Lemus, Vanessa Santos, Aiysha Thompson, Daniel Rees, Sandra Galic, John Elsworth, Bruce Kemp, Jeffrey Davies, and Zane Andrew

Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis

Peer reviewedPublisher PD

Predicting impacts of chemicals from organisms to ecosystem service delivery: A case study of endocrine disruptor effects on trout

We demonstrate how mechanistic modeling can be used to predict whether and how biological responses to chemicals at (sub)organismal levels in model species (i.e., what we typically measure) translate into impacts on ecosystem service delivery (i.e., what we care about). We consider a hypothetical case study of two species of trout, brown trout (Salmo trutta; BT) and greenback cutthroat trout (Oncorhynchus clarkii stomias; GCT). These hypothetical populations live in a high-altitude river system and are exposed to human-derived estrogen (17α‑ethinyl estradiol, EE2), which is the bioactive estrogen in many contraceptives. We use the individual based model in STREAM to explore how seasonally varying concentrations of EE2 could influence male spawning and sperm quality. Resulting impacts on trout recruitment and the consequences of such for anglers and for the continued viability of populations of GCT (the state fish of Colorado) are explored. in STREAM incorporates seasonally varying river flow and temperature, fishing pressure, the influence of EE2 on species-specific demography, and inter-specific competition. The model facilitates quantitative exploration of the relative importance of endocrine disruption and inter-species competition on trout population dynamics. Simulations predicted constant EE2 loading to have more impacts on GCT than BT. However, increasing removal of BT by anglers can enhance the persistence of GCT and offset some of the negative effects of EE2. We demonstrate how models that quantitatively link impacts of chemicals and other stressors on individual survival, growth, and reproduction to consequences for populations and ecosystem service delivery, can be coupled with ecosystem service valuation. The approach facilitates interpretation of toxicity data in an ecological context and gives beneficiaries of ecosystem services amore explicit role in management decisions. Although challenges remain, this type of approach may be particularly helpful for site-specific risk assessments and those in which trade offs and synergies among ecosystem services need to be considered

An AMPKa2-specific phospho-switch controls lysosomal targeting for activation

AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) are metabolic kinases that co-ordinate nutrient supply with cell growth. AMPK negatively regulates mTORC1, and mTORC1 reciprocally phosphorylates S345/7 in both AMPK α-isoforms. We report that genetic or torin1-induced loss of α2-S345 phosphorylation relieves suppression of AMPK signaling; however, the regulatory effect does not translate to α1-S347 in HEK293T or MEF cells. Dephosphorylation of α2-S345, but not α1-S347, transiently targets AMPK to lysosomes, a cellular site for activation by LKB1. By mass spectrometry, we find that α2-S345 is basally phosphorylated at 2.5-fold higher stoichiometry than α1-S347 in HEK293T cells and, unlike α1, phosphorylation is partially retained after prolonged mTORC1 inhibition. Loss of α2-S345 phosphorylation in endogenous AMPK fails to sustain growth of MEFs under amino acid starvation conditions. These findings uncover an α2-specific mechanism by which AMPK can be activated at lysosomes in the absence of changes in cellular energy

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse