ORCID Profile
0000-0002-8166-142X
Current Organisations
Australasian College for Emergency Medicine
,
Deakin University
,
University of Melbourne
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Publisher: American Diabetes Association
Date: 15-05-2014
DOI: 10.2337/DB13-0967
Abstract: Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.
Publisher: American Physiological Society
Date: 15-05-2016
DOI: 10.1152/AJPENDO.00513.2015
Abstract: Nitric oxide influences intramuscular signaling that affects skeletal muscle glucose uptake during exercise. The role of the main NO-producing enzyme isoform activated during skeletal muscle contraction, neuronal nitric oxide synthase-μ (nNOSμ), in modulating glucose uptake has not been investigated in a physiological exercise model. In this study, conscious and unrestrained chronically catheterized nNOSμ +/+ and nNOSμ −/− mice either remained at rest or ran on a treadmill at 17 m/min for 30 min. Both groups of mice demonstrated similar exercise capacity during a maximal exercise test to exhaustion (17.7 ± 0.6 vs. 15.9 ± 0.9 min for nNOSμ +/+ and nNOSμ −/− , respectively, P 0.05). Resting and exercise blood glucose levels were comparable between the genotypes. Very low levels of NOS activity were detected in skeletal muscle from nNOSμ −/− mice, and exercise increased NOS activity only in nNOSμ +/+ mice (4.4 ± 0.3 to 5.2 ± 0.4 pmol·mg −1 ·min −1 , P 0.05). Exercise significantly increased glucose uptake in gastrocnemius muscle (5- to 7-fold) and, surprisingly, more so in nNOSμ −/− than in nNOSμ +/+ mice ( P 0.05). This is in parallel with a greater increase in AMPK phosphorylation during exercise in nNOSμ −/− mice. In conclusion, nNOSμ is not essential for skeletal muscle glucose uptake during exercise, and the higher skeletal muscle glucose uptake during exercise in nNOSμ −/− mice may be due to compensatory increases in AMPK activation.
Publisher: American Physiological Society
Date: 05-2010
DOI: 10.1152/AJPREGU.00004.2010
Abstract: Endothelial nitric oxide synthase (eNOS) is associated with a number of physiological functions involved in the regulation of metabolism however, the functional role of eNOS is poorly understood. We tested the hypothesis that eNOS is critical to muscle cell signaling and fuel usage during exercise in vivo, using 16-wk-old catheterized (carotid artery and jugular vein) C57BL/6J mice with wild-type (WT), partial (+/−), or no expression (−/−) of eNOS. Quantitative reductions in eNOS expression (∼40%) elicited many of the phenotypic effects observed in enos −/− mice under fasted, sedentary conditions, with expression of oxidative phosphorylation complexes I to V and ATP levels being decreased, and total NOS activity and Ca 2+ /CaM kinase II Thr 286 phosphorylation being increased in skeletal muscle. Despite these alterations, exercise tolerance was markedly impaired in enos −/− mice during an acute 30-min bout of exercise. An eNOS-dependent effect was observed with regard to AMP-activated protein kinase signaling and muscle perfusion. Muscle glucose and long-chain fatty acid uptake, and hepatic and skeletal muscle glycogenolysis during the exercise bout was markedly accelerated in enos −/− mice compared with enos +/− and WT mice. Correspondingly, enos −/− mice exhibited hypoglycemia during exercise. Thus, the ablation of eNOS alters a number of physiological processes that result in impaired exercise capacity in vivo. The finding that a partial reduction in eNOS expression is sufficient to induce many of the changes associated with ablation of eNOS has implications for chronic metabolic diseases, such as obesity and insulin resistance, which are associated with reduced eNOS expression.
Publisher: Springer Science and Business Media LLC
Date: 04-12-2008
Publisher: eLife Sciences Publications, Ltd
Date: 23-10-2015
DOI: 10.7554/ELIFE.08698
Abstract: T follicular helper cells (Tfh) are critical for the longevity and quality of antibody-mediated protection against infection. Yet few signaling pathways have been identified to be unique solely to Tfh development. ROQUIN is a post-transcriptional repressor of T cells, acting through its ROQ domain to destabilize mRNA targets important for Th1, Th17, and Tfh biology. Here, we report that ROQUIN has a paradoxical function on Tfh differentiation mediated by its RING domain: mice with a T cell-specific deletion of the ROQUIN RING domain have unchanged Th1, Th2, Th17, and Tregs during a T-dependent response but show a profoundly defective antigen-specific Tfh compartment. ROQUIN RING signaling directly antagonized the catalytic α1 subunit of adenosine monophosphate-activated protein kinase (AMPK), a central stress-responsive regulator of cellular metabolism and mTOR signaling, which is known to facilitate T-dependent humoral immunity. We therefore unexpectedly uncover a ROQUIN–AMPK metabolic signaling nexus essential for selectively promoting Tfh responses.
Publisher: American Diabetes Association
Date: 21-01-2011
DOI: 10.2337/DB10-1116
Abstract: The hypothesis that high-fat (HF) feeding causes skeletal muscle extracellular matrix (ECM) remodeling in C57BL/6J mice and that this remodeling contributes to diet-induced muscle insulin resistance (IR) through the collagen receptor integrin α2β1 was tested. The association between IR and ECM remodeling was studied in mice fed chow or HF diet. Specific genetic and pharmacological murine models were used to study effects of HF feeding on ECM in the absence of IR. The role of ECM-integrin interaction in IR was studied using hyperinsulinemic-euglycemic cl s on integrin α2β1-null (itga2−/−), integrin α1β1-null (itga1−/−), and wild-type littermate mice fed chow or HF. Integrin α2β1 and integrin α1β1 signaling pathways have opposing actions. HF-fed mice had IR and increased muscle collagen (Col) III and ColIV protein the former was associated with increased transcript, whereas the latter was associated with reduced matrix metalloproteinase 9 activity. Rescue of muscle IR by genetic muscle-specific mitochondria-targeted catalase overexpression or by the phosphodiesterase 5a inhibitor, sildenafil, reversed HF feeding effects on ECM remodeling and increased muscle vascularity. Collagen remained elevated in HF-fed itga2−/− mice. Nevertheless, muscle insulin action and vascularity were increased. Muscle IR in HF-fed itga1−/− mice was unchanged. Insulin sensitivity in chow-fed itga1−/− and itga2−/− mice was not different from wild-type littermates. ECM collagen expansion is tightly associated with muscle IR. Studies with itga2−/− mice provide mechanistic insight for this association by showing that the link between muscle IR and increased collagen can be uncoupled by the absence of collagen-integrin α2β1 interaction.
Publisher: Elsevier BV
Date: 09-2009
Publisher: eLife Sciences Publications, Ltd
Date: 19-09-2018
DOI: 10.7554/ELIFE.38704
Abstract: Hypothalamic neurons respond to nutritional cues by altering gene expression and neuronal excitability. The mechanisms that control such adaptive processes remain unclear. Here we define populations of POMC neurons in mice that are activated or inhibited by insulin and thereby repress or inhibit hepatic glucose production (HGP). The proportion of POMC neurons activated by insulin was dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP, which is increased by fasting, degraded after feeding and elevated in diet-induced obesity. TCPTP-deficiency enhanced insulin signaling and the proportion of POMC neurons activated by insulin to repress HGP. Elevated TCPTP in POMC neurons in obesity and/or after fasting repressed insulin signaling, the activation of POMC neurons by insulin and the insulin-induced and POMC-mediated repression of HGP. Our findings define a molecular mechanism for integrating POMC neural responses with feeding to control glucose metabolism.
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.CMET.2015.02.006
Abstract: Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.
Publisher: Wiley
Date: 10-2005
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.CELL.2012.09.021
Abstract: Diabetes, obesity, and cancer affect upward of 15% of the world's population. Interestingly, all three diseases juxtapose dysregulated intracellular signaling with altered metabolic state. Exactly which genetic factors define stable metabolic set points in vivo remains poorly understood. Here, we show that hedgehog signaling rewires cellular metabolism. We identify a cilium-dependent Smo-Ca(2+)-Ampk axis that triggers rapid Warburg-like metabolic reprogramming within minutes of activation and is required for proper metabolic selectivity and flexibility. We show that Smo modulators can uncouple the Smo-Ampk axis from canonical signaling and identify cyclopamine as one of a new class of "selective partial agonists," capable of concomitant inhibition of canonical and activation of noncanonical hedgehog signaling. Intriguingly, activation of the Smo-Ampk axis in vivo drives robust insulin-independent glucose uptake in muscle and brown adipose tissue. These data identify multiple noncanonical endpoints that are pivotal for rational design of hedgehog modulators and provide a new therapeutic avenue for obesity and diabetes.
Publisher: The Company of Biologists
Date: 15-01-2011
DOI: 10.1242/JEB.048041
Abstract: Skeletal muscle glucose uptake increases dramatically in response to physical exercise. Moreover, skeletal muscle comprises the vast majority of insulin-sensitive tissue and is a site of dysregulation in the insulin-resistant state. The biochemical and histological composition of the muscle is well defined in a variety of species. However, the functional consequences of muscle biochemical and histological adaptations to physiological and pathophysiological conditions are not well understood. The physiological regulation of muscle glucose uptake is complex. Sites involved in the regulation of muscle glucose uptake are defined by a three-step process consisting of: (1) delivery of glucose to muscle, (2) transport of glucose into the muscle by GLUT4 and (3) phosphorylation of glucose within the muscle by a hexokinase (HK). Muscle blood flow, capillary recruitment and extracellular matrix characteristics determine glucose movement from the blood to the interstitium. Plasma membrane GLUT4 content determines glucose transport into the cell. Muscle HK activity, cellular HK compartmentalization and the concentration of the HK inhibitor glucose 6-phosphate determine the capacity to phosphorylate glucose. Phosphorylation of glucose is irreversible in muscle therefore, with this reaction, glucose is trapped and the uptake process is complete. Emphasis has been placed on the role of the glucose transport step for glucose influx into muscle with the past assertion that membrane transport is rate limiting. More recent research definitively shows that the distributed control paradigm more accurately defines the regulation of muscle glucose uptake as each of the three steps that define this process are important sites of flux control.
Publisher: Elsevier BV
Date: 11-2016
Publisher: American Physiological Society
Date: 04-2006
DOI: 10.1152/AJPENDO.00464.2005
Abstract: We compared in human skeletal muscle the effect of absolute vs. relative exercise intensity on AMP-activated protein kinase (AMPK) signaling and substrate metabolism under normoxic and hypoxic conditions. Eight untrained males cycled for 30 min under hypoxic conditions (11.5% O 2 , 111 ± 12 W, 72 ± 3% hypoxia V̇o 2 peak 72% Hypoxia) or under normoxic conditions (20.9% O 2 ) matched to the same absolute (111 ± 12 W, 51 ± 1% normoxia V̇o 2 peak 51% Normoxia) or relative (to V̇o 2 peak ) intensity (171 ± 18 W, 73 ± 1% normoxia V̇o 2 peak 73% Normoxia). Increases ( P 0.05) in AMPK activity, AMPKα Thr 172 phosphorylation, ACCβ Ser 221 phosphorylation, free AMP content, and glucose clearance were more influenced by the absolute than by the relative exercise intensity, being greatest in 73% Normoxia with no difference between 51% Normoxia and 72% Hypoxia. In contrast to this, increases in muscle glycogen use, muscle lactate content, and plasma catecholamine concentration were more influenced by the relative than by the absolute exercise intensity, being similar in 72% Hypoxia and 73% Normoxia, with both trials higher than in 51% Normoxia. In conclusion, increases in muscle AMPK signaling, free AMP content, and glucose disposal during exercise are largely determined by the absolute exercise intensity, whereas increases in plasma catecholamine levels, muscle glycogen use, and muscle lactate levels are more closely associated with the relative exercise intensity.
Publisher: Springer Science and Business Media LLC
Date: 25-09-2019
DOI: 10.1038/S41586-019-1601-9
Abstract: The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.
Publisher: American Physiological Society
Date: 09-2006
DOI: 10.1152/AJPENDO.00023.2006
Abstract: There is evidence that increasing carbohydrate (CHO) availability during exercise by raising preexercise muscle glycogen levels attenuates the activation of AMPKα2 during exercise in humans. Similarly, increasing glucose levels decreases AMPKα2 activity in rat skeletal muscle in vitro. We examined the effect of CHO ingestion on skeletal muscle AMPK signaling during exercise in nine active male subjects who completed two 120-min bouts of cycling exercise at 65 ± 1% V̇o 2 peak . In a randomized, counterbalanced order, subjects ingested either an 8% CHO solution or a placebo solution during exercise. Compared with the placebo trial, CHO ingestion significantly ( P 0.05) increased plasma glucose levels and tracer-determined glucose disappearance. Exercise-induced increases in muscle-calculated free AMP (17.7- vs. 11.8-fold), muscle lactate (3.3- vs. 1.8-fold), and plasma epinephrine were reduced by CHO ingestion. However, the exercise-induced increases in skeletal muscle AMPKα2 activity, AMPKα2 Thr 172 phosphorylation and acetyl-CoA Ser 222 phosphorylation, were essentially identical in the two trials. These findings indicate that AMPK activation in skeletal muscle during exercise in humans is not sensitive to changes in plasma glucose levels in the normal range. Furthermore, the rise in plasma epinephrine levels in response to exercise was greatly suppressed by CHO ingestion without altering AMPK signaling, raising the possibility that epinephrine does not directly control AMPK activity during muscle contraction under these conditions in vivo.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.CMET.2015.04.001
Abstract: Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.
Publisher: Elsevier BV
Date: 03-2016
Publisher: American Diabetes Association
Date: 15-11-2012
DOI: 10.2337/DB12-0029
Abstract: The sphingolipids sphingosine-1-phosphate (S1P) and ceramide are important bioactive lipids with many cellular effects. Intracellular ceramide accumulation causes insulin resistance, but sphingosine kinase 1 (SphK1) prevents ceramide accumulation, in part, by promoting its metabolism into S1P. Despite this, the role of SphK1 in regulating insulin action has been largely overlooked. Transgenic (Tg) mice that overexpress SphK1 were fed a standard chow or high-fat diet (HFD) for 6 weeks before undergoing several metabolic analyses. SphK1 Tg mice fed an HFD displayed increased SphK activity in skeletal muscle, which was associated with an attenuated intramuscular ceramide accumulation compared with wild-type (WT) littermates. This was associated with a concomitant reduction in the phosphorylation of c-jun amino-terminal kinase, a serine threonine kinase associated with insulin resistance. Accordingly, skeletal muscle and whole-body insulin sensitivity were improved in SphK1 Tg, compared with WT mice, when fed an HFD. We have identified that the enzyme SphK1 is an important regulator of lipid partitioning and insulin action in skeletal muscle under conditions of increased lipid supply.
Publisher: American Physiological Society
Date: 11-2008
DOI: 10.1152/JAPPLPHYSIOL.01371.2007
Abstract: Short-term exercise training in humans attenuates AMP-activated protein kinase (AMPK) activation during subsequent exercise conducted at the same absolute workload. Short-term 5-aminoimidazole-4-carboxyamide- ribonucleoside (AICAR) administration in rats mimics exercise training on skeletal muscle in terms of increasing insulin sensitivity, mitochondrial enzymes, and GLUT4 content, but it is not known whether these adaptations are accompanied by reduced AMPK activation during subsequent exercise. We compared the effect of 10 days of treadmill training (60 min/day) with 10 days of AICAR administration (0.5 mg/g body weight ip) on subsequent AMPK activation during 45 min of treadmill exercise in male Sprague-Dawley rats. Compared with nonexercised control rats, acute exercise significantly ( P 0.05) increased AMPKα Thr 172 phosphorylation (p-AMPKα 1.6-fold) and ACCβ Ser 218 phosphorylation (p-ACCβ 4.9-fold) in the soleus and p-ACCβ 2.2-fold in the extensor digitorum longus. Ten days of exercise training abolished the increase in soleus p-AMPKα and attenuated the increase in p-ACCβ (nonsignificant 2-fold increase). Ten days of AICAR administration also attenuated the exercise-induced increases in AMPK signaling in the soleus although not as effectively as 10 days of exercise training (nonsignificant 1.3-fold increase in p-AMPKα significant 3-fold increase in p-ACCβ). The increase in skeletal muscle 2-deoxyglucose uptake during exercise was greater after either 10 days of exercise training or AICAR administration. In conclusion, 10 days of AICAR administration substantially mimics the effect of 10 days training on attenuating skeletal muscle AMPK activation in response to subsequent exercise.
Publisher: American Diabetes Association
Date: 30-04-2018
DOI: 10.2337/DB17-1485
Abstract: Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signaling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signaling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons (Agrp-Cre Ptpn2fl/fl) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic cl s, accompanied by increased [14C]-2-deoxy-d-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice, yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp-Cre Ptpn2fl/fl mice was corrected by IR heterozygosity (Agrp-Cre Ptpn2fl/fl Insrfl/+), causally linking the effects on glucose metabolism with the IR signaling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signaling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2010
DOI: 10.1038/IJO.2010.220
Publisher: Public Library of Science (PLoS)
Date: 28-05-2015
Publisher: The Endocrine Society
Date: 2013
DOI: 10.1210/EN.2012-1847
Abstract: FTY720 is a sphingosine-1-phosphate analog that has been shown to inhibit ceramide synthesis in vitro. Because ceramide accumulation in muscle is associated with insulin resistance, we aimed to examine whether FTY720 would prevent muscle ceramide accumulation in high fat-fed mice and subsequently improve glucose homeostasis. Male C57Bl/6 mice were fed either a chow or high fat-diet (HFD) for 6 wk, after which they were treated with vehicle or FTY720 (5 mg/kg) daily for a further 6 wk. The ceramide content of muscle was examined and insulin action was assessed. Whereas the HFD increased muscle ceramide, this was prevented by FTY720 treatment. This was not associated with alterations in the expression of genes involved in sphingolipid metabolism. Interestingly, the effects of FTY720 on lipid metabolism were not limited to ceramide because FTY720 also prevented the HFD-induced increase in diacylglycerol and triacylglycerol in muscle. Furthermore, the increase in CD36 mRNA expression induced by fat feeding was prevented in muscle of FTY720-treated mice. This was associated with an attenuation of the HFD-induced increase in palmitate uptake and esterification. In addition, FTY720 improved glucose homeostasis as demonstrated by a reduction in plasma insulin, an improvement in whole-body glucose tolerance, an increase in insulin-stimulated glucose uptake, and Akt phosphorylation in muscle. In conclusion, FTY720 exerts beneficial effects on muscle lipid metabolism that prevent lipid accumulation and improve glucose tolerance in high fat-fed mice. Thus, FTY720 and other compounds that target sphingosine-1-phosphate signaling may have therapeutic potential in treating insulin resistance.
Publisher: American Physiological Society
Date: 15-08-2012
DOI: 10.1152/AJPENDO.00082.2012
Abstract: Intramyocellular triacylglycerol provides fatty acid substrate for ATP generation in contracting muscle. The protein adipose triglyceride lipase (ATGL) is a key regulator of triacylglycerol lipolysis and whole body energy metabolism at rest and during exercise, and ATGL activity is reported to be enhanced by 5′-AMP-activated protein kinase (AMPK)-mediated phosphorylation at Ser 406 in mice. This is a curious observation, because AMPK activation reduces lipolysis in several cell types. We investigated whether the phosphorylation of ATGL Ser 404 (corresponding to murine Ser 406 ) was increased during exercise in human skeletal muscle and with pharmacological AMPK activation in myotubes in vitro. In human experiments, skeletal muscle and venous blood s les were obtained from recreationally active male subjects before and at 5 and 60 min during exercise. ATGL Ser 404 phosphorylation was not increased from rest during exercise, but ATGL Ser 404 phosphorylation correlated with myosin heavy chain 1 expression, suggesting a possible fiber type dependency. ATGL Ser 404 phosphorylation was not related to increases in AMPK activity, and immunoprecipitation experiments indicated no interaction between AMPK and ATGL. Rather, ATGL Ser 404 phosphorylation was associated with protein kinase A (PKA) signaling. ATGL Ser 406 phosphorylation in C 2 C 12 myotubes was unaffected by 5-aminoimidazole-4-carboxaminde-1-β-d-ribofuranoside, an AMPK activator, and the PKA activator forskolin. Our results demonstrate that ATGL Ser 404 phosphorylation is not increased in mixed skeletal muscle during moderate-intensity exercise and that AMPK does not appear to be an activating kinase for ATGL Ser 404/406 in skeletal muscle.
Publisher: Wiley
Date: 03-01-2021
Abstract: With most paediatric emergency research in Australia conducted at tertiary EDs, it is important to understand how presentations differ between those at tertiary paediatric EDs and all other EDs. Retrospective epidemiological study assessing paediatric case‐mix and time‐based performance metrics (aged 0–14 years) obtained from a national health service minimum dataset for the 2017–2018 financial year, comparing tertiary paediatric EDs and all other EDs. We defined a ‘major tertiary paediatric hospital’ as one which was accredited for training in both paediatric emergency medicine and paediatric intensive care. Of the 1 695 854 paediatric ED presentations, 23.8% were seen in nine major metropolitan tertiary paediatric hospitals. Reasons for presentations were more distinctive between cohorts among children aged 10–14 years, where psychiatric illness (5.2% vs 2.5%) and neurological illness (4.5% vs 2.5%) were more commonly seen in major tertiary paediatric EDs. Australian Indigenous children were significantly less likely to present to tertiary paediatric EDs (3.0%), compared with other EDs (9.7%) (odds ratio 0.27, 95% confidence interval 0.26–0.27). While median waiting times were longer in major tertiary paediatric EDs (28 min [interquartile range 11–65]) than in other EDs (20 min [interquartile range 8–48], P 0.001), patients were also less likely to leave without being seen (5.5% in tertiary paediatric EDs vs 6.9% in other EDs odds ratio 0.80, 95% confidence interval 0.78–0.81). The present study identified key areas of difference in paediatric presentations between tertiary paediatric EDs and other EDs. It is vital to broaden paediatric ED research beyond tertiary paediatric centres, to ensure relevance and generalisability.
Publisher: American Physiological Society
Date: 08-2012
DOI: 10.1152/AJPENDO.00667.2011
Abstract: Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components. A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance. This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise.
Publisher: American Physiological Society
Date: 08-2007
DOI: 10.1152/AJPREGU.00796.2006
Abstract: The major isoform of nitric oxide synthase (NOS) in skeletal muscle is the splice variant of neuronal NOS, termed nNOSμ. Exercise training increases nNOSμ protein levels in rat skeletal muscle, but data in humans are conflicting. We performed two studies to determine 1) whether resting nNOSμ protein expression is greater in skeletal muscle of 10 endurance-trained athletes compared with 11 sedentary in iduals ( study 1) and 2) whether intense short-term (10 days) exercise training increases resting nNOSμ protein (within whole muscle and also within types I, IIa, and IIx fibers) in eight sedentary in iduals ( study 2). In study 1, nNOSμ protein was ∼60% higher ( P 0.05) in endurance-trained athletes compared with the sedentary participants. In study 2, nNOSμ protein expression was similar in types I, IIa, and IIx fibers before training. Ten days of intense exercise training significantly ( P 0.05) increased nNOSμ protein levels in types I, IIa, and IIx fibers, a finding that was validated by using whole muscle s les. Endothelial NOS and inducible NOS protein were barely detectable in the skeletal muscle s les. In conclusion, nNOSμ protein expression is greater in endurance-trained in iduals when compared with sedentary in iduals. Ten days of intense exercise is also sufficient to increase nNOSμ expression in untrained in iduals, due to uniform increases of nNOSμ within types I, IIa, and IIx fibers.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2008
Publisher: Springer Science and Business Media LLC
Date: 08-12-2012
Publisher: Springer Science and Business Media LLC
Date: 26-04-2013
DOI: 10.1007/S00125-013-2913-1
Abstract: While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD). C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle. Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic cl , was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance. HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.
Publisher: American Physiological Society
Date: 2006
DOI: 10.1152/AJPENDO.00263.2005
Abstract: Nitric oxide synthase (NOS) inhibition has been shown in humans to attenuate exercise-induced increases in muscle glucose uptake. We examined the effect of infusing the NO precursor l-arginine (l-Arg) on glucose kinetics during exercise in humans. Nine endurance-trained males cycled for 120 min at 72 ± 1% V̇o 2 peak followed immediately by a 15-min “all-out” cycling performance bout. A [6,6- 2 H]glucose tracer was infused throughout exercise, and either saline alone (Control, CON) or saline containing l-Arg HCl (l-Arg, 30 g at 0.5 g/min) was coinfused in a double-blind, randomized order during the last 60 min of exercise. l-Arg augmented the increases in glucose rate of appearance, glucose rate of disappearance, and glucose clearance rate (l-Arg: 16.1 ± 1.8 ml·min −1 ·kg −1 CON: 11.9 ± 0.7 ml·min −1 ·kg −1 at 120 min, P 0.05) during exercise, with a net effect of reducing plasma glucose concentration during exercise. l-Arg infusion had no significant effect on plasma insulin concentration but attenuated the increase in nonesterified fatty acid and glycerol concentrations during exercise. l-Arg infusion had no effect on cycling exercise performance. In conclusion, l-Arg infusion during exercise significantly increases skeletal muscle glucose clearance in humans. Because plasma insulin concentration was unaffected by l-Arg infusion, greater NO production may have been responsible for this effect.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2014
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.BBALIP.2014.12.002
Abstract: Hepatic insulin resistance is a major risk factor for the development of type 2 diabetes and is associated with the accumulation of lipids, including diacylglycerol (DAG), triacylglycerols (TAG) and ceramide. There is evidence that enzymes involved in ceramide or sphingolipid metabolism may have a role in regulating concentrations of glycerolipids such as DAG and TAG. Here we have investigated the role of sphingosine kinase (SphK) in regulating hepatic lipid levels. We show that mice on a high-fat high-sucrose diet (HFHS) displayed glucose intolerance, elevated liver TAG and DAG, and a reduction in total hepatic SphK activity. Reduced SphK activity correlated with downregulation of SphK1, but not SphK2 expression, and was not associated with altered ceramide levels. The role of SphK1 was further investigated by overexpressing this isoform in the liver of mice in vivo. On a low-fat diet (LFD) mice overexpressing liver SphK1, displayed reduced hepatic TAG synthesis and total TAG levels, but with no change to DAG or ceramide. These mice also exhibited no change in gluconeogenesis, glycogenolysis or glucose tolerance. Similarly, overexpression of SphK1 had no effect on the pattern of endogenous glucose production determined during a glucose tolerance test. Under HFHS conditions, normalization of liver SphK activity to levels observed in LFD controls did not alter hepatic TAG concentrations. Furthermore, DAG, ceramide and glucose tolerance were also unaffected. In conclusion, our data suggest that SphK1 plays an important role in regulating TAG metabolism under LFD conditions.
Publisher: American Diabetes Association
Date: 10-2007
DOI: 10.2337/DB07-0532
Abstract: OBJECTIVE—Muscle glucose uptake (MGU) is regulated by glucose delivery to, transport into, and phosphorylation within muscle. The aim of this study was to determine the role of limitations in glucose phosphorylation in the control of MGU during either physiological insulin stimulation (4 mU · kg−1· min−1) or exercise with chow or high-fat feeding. RESEARCH DESIGN AND METHODS—C57BL/6J mice with (HK+/−) and without (WT) a 50% hexokinase (HK) II deletion were fed chow or high-fat diets and studied at 4 months of age during a 120-min insulin cl or 30 min of treadmill exercise (n = 8–10 mice/group). 2-deoxy[3H]glucose was used to measure Rg, an index of MGU. RESULTS—Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK+/−). Both high-fat feeding and partial HK II knockout independently created fasting hyperinsulinemia, a response that was increased synergistically with combined high-fat feeding and HK II knockout. Whole-body insulin action was suppressed by ∼25% with either high-fat feeding or partial HK II knockout alone but by & % when the two were combined. Insulin-stimulated Rg was modestly impaired by high-fat feeding and partial HK II knockout independently (∼15–20%) but markedly reduced by the two together (∼40–50%). Exercise-stimulated Rg was reduced by ∼50% with high-fat feeding and partial HK II knockout alone and was not attenuated further by combining the two. CONCLUSIONS—In summary, impairments in whole-body metabolism and MGU due to high-fat feeding and partial HK II knockout combined during insulin stimulation are additive. In contrast, combining high-fat feeding and partial HK II knockout during exercise causes no greater impairment in MGU than the two manipulations independently. This suggests that MGU is impaired during exercise by high-fat feeding due to, in large part, a limitation in glucose phosphorylation. Together, these studies show that the high-fat–fed mouse is characterized by defects at multiple steps of the MGU system that are precipitated by different physiological conditions.
Publisher: American Physiological Society
Date: 07-2009
DOI: 10.1152/JAPPLPHYSIOL.91208.2008
Abstract: AMP-activated protein kinase (AMPK) has been extensively studied in whole muscle biopsy s les of humans, yet the fiber type-specific expression and/or activation of AMPK is unknown. We examined basal and exercise AMPK-α Thr 172 phosphorylation and AMPK subunit expression (α 1 , α 2 , and γ 3 ) in type I, IIa, and IIx fibers of human skeletal muscle before and after 10 days of exercise training. Before training basal AMPK phosphorylation was greatest in type IIa fibers ( P 0.05 vs. type I and IIx), while an acute bout of exercise increased AMPK phosphorylation in all fibers ( P 0.05), with the greatest increase occurring in type IIx fibers. Exercise training significantly increased basal AMPK phosphorylation in all fibers, and the exercise-induced increases were uniformly suppressed compared with pretraining exercise. Expression of AMPK-α 1 and -α 2 was similar between fibers and was not altered by exercise training. However, AMPK-γ 3 was differentially expressed in skeletal muscle fibers (type IIx type IIa type I), irrespective of training status. Thus skeletal muscle AMPK phosphorylation and AMPK expression are fiber type specific in humans in the basal state, as well as during exercise. Our findings reveal fiber type-specific differences that have been masked in previous studies examining mixed muscle s les.
Publisher: American Society for Clinical Investigation
Date: 03-08-2009
DOI: 10.1172/JCI38650
Publisher: American Physiological Society
Date: 15-10-2012
DOI: 10.1152/JAPPLPHYSIOL.01344.2011
Abstract: The objective of this study was to test the hypothesis that exercise-stimulated muscle glucose uptake (MGU) is augmented by increasing mitochondrial reactive oxygen species (mtROS) scavenging capacity. This hypothesis was tested in genetically altered mice fed chow or a high-fat (HF) diet that accelerates mtROS formation. Mice overexpressing SOD2 ( sod2 Tg ), mitochondria-targeted catalase ( mcat Tg ), and combined SOD2 and mCAT (mtAO) were used to increase mtROS scavenging. mtROS was assessed by the H 2 O 2 emitting potential ( JH 2 O 2 ) in muscle fibers. sod2 Tg did not decrease JH 2 O 2 in chow-fed mice, but decreased JH 2 O 2 in HF-fed mice. mcat Tg and mtAO decreased JH 2 O 2 in both chow- and HF-fed mice. In parallel, the ratio of reduced to oxidized glutathione (GSH/GSSG) was unaltered in sod2 Tg in chow-fed mice, but was increased in HF-fed sod2 Tg and both chow- and HF-fed mcat Tg and mtAO. Nitrotyrosine, a marker of NO-dependent, reactive nitrogen species (RNS)-induced nitrative stress, was decreased in both chow- and HF-fed sod2 Tg , mcat Tg , and mtAO mice. This effect was not changed with exercise. Kg, an index of MGU was assessed using 2-[ 14 C]-deoxyglucose during exercise. In chow-fed mice, sod2 Tg , mcat Tg , and mtAO increased exercise Kg compared with wild types. Exercise Kg was also augmented in HF-fed sod2 Tg and mcat Tg mice but unchanged in HF-fed mtAO mice. In conclusion, mtROS scavenging is a key regulator of exercise-mediated MGU and this regulation depends on nutritional state.
Location: United States of America
Start Date: 2013
End Date: 2016
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2012
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2011
End Date: 2013
Funder: National Health and Medical Research Council
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