%0 Journal Article
%~ PubMed
%A Watt, Matthew J
%A Hoy, Andrew J
%A Muoio, Deborah M
%A Coleman, Rosalind A
%T Distinct roles of specific fatty acids in cellular processes: implications for interpreting and reporting experiments.
%B American Journal of Physiology: Endocrinology and Metabolism
%D 2012
%C United States
%I American Physiological Society
%V 302
%N 1
%P E1-E3
%@ 1522-1555
%X Plasma contains a variety of long-chain fatty acids (FAs), such that about 35% are saturated and 65% are unsaturated. There are countless examples that show how different FAs impart specific and unique effects, or even opposing actions, on cellular function. Despite these differing effects, palmitate (C16:0) is regularly used to represent "FAs" in cell based experiments. Although palmitate can be useful to induce and study stress effects in cultured cells, these effects in isolation are not physiologically relevant to dietary manipulations, obesity, or the consequences of physiological concentrations of FAs. Hence, authors should avoid conclusions that generalize about "FAs" or "saturated FAs" or "high-fat diet" effects if only a single FA was used in the reported experiments.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Watt, Matthew J
%A Hoy, Andrew J
%T Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function.
%B American Journal of Physiology: Endocrinology and Metabolism
%D 2012
%C United States
%I American Physiological Society
%V 302
%N 11
%P E1315-E1328
%@ 1522-1555
%X Fatty acids derived from adipose tissue lipolysis, intramyocellular triacylglycerol lipolysis or de novo lipogenesis serve a variety of functions in skeletal muscle. The two major fates of fatty acids are mitochondrial oxidation to provide energy for the myocyte and storage within a variety of lipids, where they are primarily stored in discrete lipid droplets or serve as important structural components of membranes. In this review, we provide a brief overview of skeletal muscle fatty acid metabolism and highlight recent notable advances in the field. We then discuss (1) how lipids are stored in and mobilized from various subcellular locations to provide adaptive or maladaptive signals in the myocyte and (2) outline how lipid metabolites or metabolic by-products derived from the actions of triacylglycerol metabolism or ?-oxidation act as positive and negative regulators of insulin action. We have placed an emphasis on recent developments in the lipid biology field with respect to understanding skeletal muscle physiology and discuss unanswered questions and technical limitations for assessing lipid signaling in skeletal muscle.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Watt, M J
%A Barnett, A C
%A Bruce, C R
%A Schenk, S
%A Horowitz, J F
%A Hoy, A J
%T Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide.
%B Diabetologia
%D 2012
%C Germany
%I Springer
%V 55
%N 10
%P 2741-2746
%@ 0012-186X
%X 
%Z FOR Codes: 110307 110104


%0 Journal Article
%~ PubMed
%A Turpin, S M
%A Hoy, A J
%A Brown, R D
%A Rudaz, C Garcia
%A Honeyman, J
%A Matzaris, M
%A Watt, M J
%T Adipose triacylglycerol lipase is a major regulator of hepatic lipid metabolism but not insulin sensitivity in mice.
%B Diabetologia
%D 2011
%C Germany
%I Springer
%V 54
%N 1
%P 146-156
%@ 0012-186X
%X Hepatic steatosis is characterised by excessive triacylglycerol accumulation and is strongly associated with insulin resistance. An inability to efficiently mobilise liver triacylglycerol may be a key event mediating hepatic steatosis. Adipose triacylglycerol lipase (ATGL) is a key triacylglycerol lipase in the liver and we hypothesised that liver-specific overproduction of ATGL would reduce steatosis and enhance insulin action in obese rodents.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Hoy, Andrew J
%A Bruce, Clinton R
%A Turpin, Sarah M
%A Morris, Alexander J
%A Febbraio, Mark A
%A Watt, Matthew J
%T Adipose triglyceride lipase-null mice are resistant to high-fat diet-induced insulin resistance despite reduced energy expenditure and ectopic lipid accumulation.
%B Endocrinology
%D 2011
%C United States
%I The Endocrine Society
%V 152
%N 1
%P 48-58
%@ 0013-7227
%X Adipose triglyceride lipase (ATGL) null (-/-) mice store vast amounts of triacylglycerol in key glucoregulatory tissues yet exhibit enhanced insulin sensitivity and glucose tolerance. The mechanisms underpinning these divergent observations are unknown but may relate to the reduced availability of circulating fatty acids. The aim of this study was to determine whether the enhancements in insulin stimulated glucose metabolism in ATGL-/- mice persist when challenged with a high-fat diet. ATGL-/- mice fed a low-fat diet exhibit improved whole-body insulin sensitivity and glucose tolerance compared with wild-type mice. Wild-type mice became hyperlipidemic and insulin-resistant when challenged with a high-fat diet (HFD, 60% fat) for 4 wk. ATGL-/- mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to pre-high-fat diet levels and were refractory to glucose intolerance and insulin resistance. This protection from high-fat diet-induced metabolic perturbations was associated with a preference for fatty acid utilization but reduced energy expenditure and no change in markers of mitochondrial capacity or density. The protection from high-fat diet-induced insulin resistance in ATGL-/- mice was due to increased cardiac and liver insulin-stimulated glucose clearance despite increased lipid content in these tissues. Additionally, there was no difference in skeletal muscle insulin-stimulated glucose disposal, but there was a reduction observed in brown adipose tissue. Overall, these results show that ATGL-/- mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Wright, L E
%A Brandon, A E
%A Hoy, A J
%A Forsberg, G-B
%A Lelliott, C J
%A Reznick, J
%A Löfgren, L
%A Oscarsson, J
%A Strömstedt, M
%A Cooney, G J
%A Turner, N
%T Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1? involves reductions in long-chain acyl-CoA levels and oxidative stress.
%B Diabetologia
%D 2011
%C Germany
%I Springer
%V 54
%N 6
%P 1417-26
%@ 0012-186X
%X To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1?? [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Brandon, Amanda E
%A Hoy, Andrew J
%A Wright, Lauren E
%A Turner, Nigel
%A Hegarty, Bronwyn D
%A Iseli, Tristan J
%A Julia Xu, X
%A Cooney, Gregory J
%A Saha, Asish K
%A Ruderman, Neil B
%A Kraegen, Edward W
%T The evolution of insulin resistance in muscle of the glucose infused rat.
%B Archives of Biochemistry and Biophysics
%D 2011
%C United States
%I Academic Press
%V 509
%N 2
%P 133-141
%@ 1096-0384
%X 
%Z FOR Codes: 110107 110306


%0 Journal Article
%~ PubMed
%A Hoehn, Kyle L
%A Turner, Nigel
%A Swarbrick, Michael M
%A Wilks, Donna
%A Preston, Elaine
%A Phua, Yuwei
%A Joshi, Himani
%A Furler, Stuart M
%A Larance, Mark
%A Hegarty, Bronwyn D
%A Leslie, Simon J
%A Pickford, Russell
%A Hoy, Andrew J
%A Kraegen, Edward W
%A James, David E
%A Cooney, Gregory J
%T Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity.
%B Cell Metabolism
%D 2010
%C United States
%I Cell Press
%V 11
%N 1
%P 70-76
%@ 1932-7420
%X Activation of AMP-activated protein kinase (AMPK) is thought to convey many of the beneficial effects of exercise via its inhibitory effect on acetyl-CoA carboxylase 2 (ACC2) and promotion of fatty acid oxidation. Hence, AMPK and ACC have become major drug targets for weight loss and improved insulin action. However, it remains unclear whether or how activation of the fatty acid oxidation pathway without a concomitant increase in energy expenditure could be beneficial. Here, we have used either pharmacological (administration of the AMPK agonist 5('') aminoimidazole-4-carboxamide-riboside) or genetic means (mutation of the ACC2 gene in mice) to manipulate fatty acid oxidation to determine whether this is sufficient to promote leanness. Both of these strategies increased whole-body fatty acid oxidation without altering energy expenditure or adiposity. We conclude that negative energy balance is a prerequisite for weight reduction, and increased fatty acid oxidation per se has little, if any, effect to reduce adiposity.
%Z FOR Codes: 60104


%0 Journal Article
%~ PubMed
%A Hoehn, Kyle L
%A Salmon, Adam B
%A Hohnen-Behrens, Cordula
%A Turner, Nigel
%A Hoy, Andrew J
%A Maghzal, Ghassan J
%A Stocker, Roland
%A Van Remmen, Holly
%A Kraegen, Edward W
%A Cooney, Greg J
%A Richardson, Arlan R
%A James, David E
%T Insulin resistance is a cellular antioxidant defense mechanism.
%B Proceedings of the National Academy of Sciences of the United States of America
%D 2009
%C United States
%I National Academy of Sciences
%V 106
%N 42
%P 17787-17792
%@ 0027-8424
%X We know a great deal about the cellular response to starvation via AMPK, but less is known about the reaction to nutrient excess. Insulin resistance may be an appropriate response to nutrient excess, but the cellular sensors that link these parameters remain poorly defined. In the present study we provide evidence that mitochondrial superoxide production is a common feature of many different models of insulin resistance in adipocytes, myotubes, and mice. In particular, insulin resistance was rapidly reversible upon exposure to agents that act as mitochondrial uncouplers, ETC inhibitors, or mitochondrial superoxide dismutase (MnSOD) mimetics. Similar effects were observed with overexpression of mitochondrial MnSOD. Furthermore, acute induction of mitochondrial superoxide production using the complex III antagonist antimycin A caused rapid attenuation of insulin action independently of changes in the canonical PI3K/Akt pathway. These results were validated in vivo in that MnSOD transgenic mice were partially protected against HFD induced insulin resistance and MnSOD+/- mice were glucose intolerant on a standard chow diet. These data place mitochondrial superoxide at the nexus between intracellular metabolism and the control of insulin action potentially defining this as a metabolic sensor of energy excess.
%Z FOR Codes: 110107


%0 Journal Article
%A Hoy, Andrew
%A Watt, Matthew J
%T Lipid Partitioning and Insulin Sensitivity: Lessons learnt
from Genetic Models
%B Asia-Pacific Journal of Endocrinology
%D 2009
%C United Kingdom
%I San Lucas Medical Limited
%V 1
%N 1
%P 35-47
%@ 2041-7993
%X 
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Hoy, Andrew J
%A Brandon, Amanda E
%A Turner, Nigel
%A Watt, Matthew J
%A Bruce, Clinton R
%A Cooney, Gregory J
%A Kraegen, Edward W
%T Lipid and insulin infusion-induced skeletal muscle insulin resistance is likely due to metabolic feedback and not changes in IRS-1, Akt, or AS160 phosphorylation.
%B American Journal of Physiology: Endocrinology and Metabolism
%D 2009
%C United States
%I American Physiological Society
%V 297
%N 1
%P E67-E75
%@ 1522-1555
%X Type 2 diabetes is characterized by hyperlipidemia, hyperinsulinemia, and insulin resistance. The aim of this study was to investigate whether acute hyperlipidemia-induced insulin resistance in the presence of hyperinsulinemia was due to defective insulin signaling. Hyperinsulinemia (approximately 300 mU/l) with hyperlipidemia or glycerol (control) was produced in cannulated male Wistar rats for 0.5, 1 h, 3 h, or 5 h. The glucose infusion rate required to maintain euglycemia was significantly reduced by 3 h with lipid infusion and was further reduced after 5 h of infusion, with no difference in plasma insulin levels, indicating development of insulin resistance. Consistent with this finding, in vivo skeletal muscle glucose uptake (31%, P < 0.05) and glycogen synthesis rate (38%, P < 0.02) were significantly reduced after 5 h compared with 3 h of lipid infusion. Despite the development of insulin resistance, there was no difference in the phosphorylation state of multiple insulin-signaling intermediates or muscle diacylglyceride and ceramide content over the same time course. However, there was an increase in cumulative exposure to long-chain acyl-CoA (70%) with lipid infusion. Interestingly, although muscle pyruvate dehydrogenase kinase 4 protein content was decreased in hyperinsulinemic glycerol-infused rats, this decrease was blunted in muscle from hyperinsulinemic lipid-infused rats. Decreased pyruvate dehydrogenase complex activity was also observed in lipid- and insulin-infused animals (43%). Overall, these results suggest that acute reductions in muscle glucose metabolism in rats with hyperlipidemia and hyperinsulinemia are more likely a result of substrate competition than a significant early defect in insulin action or signaling.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Bruce, Clinton R
%A Hoy, Andrew J
%A Turner, Nigel
%A Watt, Matthew J
%A Allen, Tamara L
%A Carpenter, Kevin
%A Cooney, Gregory J
%A Febbraio, Mark A
%A Kraegen, Edward W
%T Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance.
%B Diabetes
%D 2009
%C United States
%I American Diabetes Association
%V 58
%N 3
%P 550-558
%@ 0012-1797
%X OBJECTIVE: Skeletal muscle insulin resistance is associated with lipid accumulation, but whether insulin resistance is due to reduced or enhanced flux of long-chain fatty acids into the mitochondria is both controversial and unclear. We hypothesized that skeletal muscle-specific overexpression of the muscle isoform of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acyl CoA into mitochondria, would enhance rates of fatty acid oxidation and improve insulin action in muscle in high-fat diet insulin-resistant rats. RESEARCH DESIGN AND METHODS: Rats were fed a standard (chow) or high-fat diet for 4 weeks. After 3 weeks, in vivo electrotransfer was used to overexpress the muscle isoform of CPT1 in the distal hindlimb muscles (tibialis anterior and extensor digitorum longus [EDL]). Skeletal muscle insulin action was examined in vivo during a hyperinsulinemic-euglycemic clamp. RESULTS: In vivo electrotransfer produced a physiologically relevant increase of approximately 20% in enzyme activity; and although the high-fat diet produced insulin resistance in the sham-treated muscle, insulin action was improved in the CPT1-overexpressing muscle. This improvement was associated with a reduction in triacylglycerol content, the membrane-to-cytosolic ratio of diacylglycerol, and protein kinase C theta activity. Importantly, overexpression of CPT1 did not affect markers of mitochondrial capacity or function, nor did it alter skeletal muscle acylcarnitine profiles irrespective of diet. CONCLUSIONS: Our data provide clear evidence that a physiological increase in the capacity of long-chain fatty acyl CoA entry into mitochondria is sufficient to ameliorate lipid-induced insulin resistance in muscle.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Hoy, A J
%A Peoples, G E
%A McLennan, P L
%T The effect of vasoconstrictors on oxygen consumption in resting and contracting skeletal muscle of the autologous pump-perfused rat hindlimb.
%B Journal of Physiology and Pharmacology
%D 2009
%C Poland
%I Polskie Towarzystwo Fizjologiczne
%V 60
%N 3
%P 155-160
%@ 1899-1505
%X This study used a novel in vivo model to test the hypothesis that nutritive and non-nutritive blood flow distribution can still be observed under conditions of high vascular tone and oxygen delivery at rest and in metabolically active (twitch contracting) skeletal muscle. Experiments were performed in a constant flow autologous pump-perfused hindlimb in anaesthetised male Wistar rats. Agonists were tested at rest with a flow rate of 1ml x min(-1), and during hindlimb muscle twitch contractions (sciatic nerve stimulation: 6V, 1Hz, 0.05ms, 3min) at a flow rate of 2ml x min(-1). Oxygen consumption was determined from hindlimb venous and arterial blood samples. Resting perfusion pressure at 1ml x min(-1) was 92 + or - 3 mmHg (N=15) and oxygen consumption was 0.41 + or - 0.05 micromol x min(-1) x g(-1). Serotonin increased perfusion pressure and significantly decreased basal hindlimb oxygen consumption at rest. During acute muscle contraction this effect on oxygen consumption was diminished. Noradrenaline significantly increased perfusion pressure but had no significant effect on basal hindlimb oxygen consumption. Vasoconstriction that impacts upon muscle metabolism occurs in vivo, which potentially could be due to selective redistribution of blood flow. However, during muscle contraction local release of vasodilatory regulation can overcome exogenously-induced vasoconstriction. These results support the hypothesis that dual vascular pathways may explain differential vasoconstriction and how it impacts upon muscle metabolism.
%Z FOR Codes: 111501


%0 Journal Article
%~ PubMed
%A Hoy, Andrew J
%A Turner, Nigel
%T New insight into the mechanism by which acute physical exercise ameliorates insulin resistance.
%B Journal of Physiology
%D 2008
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 586
%N 9
%P 2251-2252
%@ 1469-7793
%X 
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Hoy, Andrew J
%A Bruce, Clinton R
%A Cederberg, Anna
%A Turner, Nigel
%A James, David E
%A Cooney, Gregory J
%A Kraegen, Edward W
%T Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation.
%B American Journal of Physiology: Endocrinology and Metabolism
%D 2007
%C United States
%I American Physiological Society
%V 293
%N 5
%P E1358-E1364
%@ 0193-1849
%X Hyperglycemia is a defining feature of Type 1 and 2 diabetes. Hyperglycemia also causes insulin resistance, and our group (Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ, Ruderman NB. Am J Physiol Endocrinol Metab Endocrinol Metab 290: E471-E479, 2006) has recently demonstrated that hyperglycemia generated by glucose infusion results in insulin resistance after 5 h but not after 3 h. The aim of this study was to investigate possible mechanism(s) by which glucose infusion causes insulin resistance in skeletal muscle and in particular to examine whether this was associated with changes in insulin signaling. Hyperglycemia (~10 mM) was produced in cannulated male Wistar rats for up to 5 h. The glucose infusion rate required to maintain this hyperglycemia progressively lessened over 5 h (by 25%, P < 0.0001 at 5 h) without any alteration in plasma insulin levels consistent with the development of insulin resistance. Muscle glucose uptake in vivo (44%; P < 0.05) and glycogen synthesis rate (52%; P < 0.001) were reduced after 5 h compared with after 3 h of infusion. Despite these changes, there was no decrease in the phosphorylation state of multiple insulin signaling intermediates [insulin receptor, Akt, AS160 (Akt substrate of 160 kDa), glycogen synthase kinase-3beta] over the same time course. In isolated soleus strips taken from control or 1- or 5-h glucose-infused animals, insulin-stimulated 2-deoxyglucose transport was similar, but glycogen synthesis was significantly reduced in the 5-h muscle sample (68% vs. 1-h sample; P < 0.001). These results suggest that the reduced muscle glucose uptake in rats after 5 h of acute hyperglycemia is due more to the metabolic effects of excess glycogen storage than to a defect in insulin signaling or glucose transport.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Kraegen, Edward W
%A Saha, Asish K
%A Preston, Elaine
%A Wilks, Donna
%A Hoy, Andrew J
%A Cooney, Gregory J
%A Ruderman, Neil B
%T Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats.
%B American Journal of Physiology: Endocrinology and Metabolism
%D 2006
%C United States
%I American Physiological Society
%V 290
%N 3
%P E471-E479
%@ 0193-1849
%X Glucose infusion in rats for 1-4 days results in insulin resistance and increased triglyceride, whole tissue long-chain fatty acyl-CoA (LCA-CoA), and malonyl-CoA content in red skeletal muscle. Despite this, the relation between these alterations and the onset of insulin resistance has not been defined. We aimed to 1) identify whether the changes in these lipids and of diacylglycerol (DAG) precede or accompany the onset of insulin resistance in glucose-infused rats, 2) determine whether the insulin resistance is associated with alterations in AMP-activated protein kinase (AMPK), and 3) assess whether similar changes occur in liver and in muscle. Hyperglycemia (17-18 mM) was maintained by intravenous glucose infusion in rats for 3 or 5 h; then euglycemia was restored and a 2-h hyperinsulinemic clamp was performed. Significant (P < 0.01) muscle and liver insulin resistance first appeared in red quadriceps and liver of the glucose-infused group at 5 h and was associated with a twofold increase in DAG and malonyl-CoA content and a 50% decrease in AMPK and acetyl-CoA carboxylase (ACC) phosphorylation and AMPK activity. White quadriceps showed qualitatively similar changes but without decreases in AMPK or ACC phosphorylation. Triglyceride mass was increased at 5 h only in liver, and whole tissue LCA-CoA content was not increased in liver or either muscle type. We conclude that the onset of insulin resistance induced by glucose oversupply correlates temporally with increases in malonyl-CoA and DAG content in all three tissues and with reduced AMPK phosphorylation and activity in red muscle and liver. In contrast, it was not associated with increased whole tissue LCA-CoA content in any tissue or triglyceride in muscle, although both are observed at later times.
%Z FOR Codes: 110306


%0 Journal Article
%~ PubMed
%A Ye, Ji-Ming
%A Dzamko, Nick
%A Hoy, Andrew J
%A Iglesias, Miguel A
%A Kemp, Bruce
%A Kraegen, Edward
%T Rosiglitazone treatment enhances acute AMP-activated protein kinase-mediated muscle and adipose tissue glucose uptake in high-fat-fed rats.
%B Diabetes
%D 2006
%C United States
%I American Diabetes Association
%V 55
%N 10
%P 2797-2804
%@ 0012-1797
%X AMP-activated protein kinase (AMPK) has been implicated in the insulin-sensitizing actions of thiazolidinediones (TZDs), but it is not known whether TZD treatment can enhance tissue glucose uptake in response to AMPK activation. The present study investigated the influence of the TZD rosiglitazone on glucose turnover induced by intravenous infusion of the AMPK activator 5-aminoimidazole 4-carboxamide riboside (AICAR) under euglycemic and iso-insulinemic conditions in insulin-resistant high-fat-fed rats. We found that rosiglitazone treatment significantly enhanced AICAR-stimulated whole-body glucose disposal by 27% in high-fat-fed rats, and a 44% greater glucose infusion rate (both P < 0.01 vs. vehicle control rats) was required to maintain euglycemia. Along with this, both AICAR-stimulated glucose uptake and glucose incorporation into glycogen in muscle and adipose tissue were enhanced (P < 0.05). The enhanced glucose uptake and glycogen synthesis in muscle were associated with increased activity of total AMPK and the AMPKalpha2 subunit. In comparison, these effects were not apparent in rats fed standard rodent diet. Thus, our findings suggest that in addition to ameliorating insulin resistance, TZDs may enhance AMPK-stimulated glucose clearance into peripheral tissues in insulin-resistant states.
%Z FOR Codes: 110306