Andrew Hoy | The University of Sydney (original) (raw)

Papers by Andrew Hoy

Molecular and cellular biochemistry, Jan 23, 2016

Annexin A6 (AnxA6) is a lipid-binding protein highly expressed in the liver, regulating cholester... more Annexin A6 (AnxA6) is a lipid-binding protein highly expressed in the liver, regulating cholesterol homeostasis and signaling pathways with a role in liver physiology. Here, we analyzed whether hepatic AnxA6 levels are affected by pathological conditions that are associated with liver dysfunction and liver injury. AnxA6 levels in the fatty liver of mice fed a high-fat diet, in ob/ob and db/db animals and in human fatty liver are comparable to controls. Similarly, AnxA6 levels appear unaffected in murine nonalcoholic steatohepatitis and human liver fibrosis. Accordingly, adiponectin, lysophosphatidylcholine, palmitate, and TGFbeta, all of which have a role in liver injury, do not affect AnxA6 expression in human hepatocytes. Likewise, adiponectin and IL8 do not alter AnxA6 levels in primary human hepatic stellate cells. However, in hepatic tumors of 18 patients, AnxA6 protein levels are substantially reduced compared to nontumorous tissues. AnxA6 mRNA is even increased in the tumors ...

American Journal of Physiology Endocrinology and Metabolism, Mar 1, 2006

Ruderman. Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany in... more Ruderman. Increased malonyl-CoA and diacylglycerol content and reduced AMPK activity accompany insulin resistance induced by glucose infusion in muscle and liver of rats. 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 Ͻ 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. adenosine monophosphate-activated protein kinase; hyperglycemia; glucose clamp; triglyceride; long-chain acyl-coenzyme A; glucotoxicity CHRONIC HYPERGLYCEMIA IS INCREASINGLY RECOGNIZED as a factor contributing to the insulin resistance and impaired insulin secretion associated with diabetes (48). It has been linked to insulin resistance in type 1 diabetic subjects in poor glycemic control (51) and in muscle and liver (10) of rodents infused with glucose for 1-5 days. In addition, prolonged exposure of muscle (4 h) (38) and vascular endothelium

Journal of Physiology and Pharmacology an Official Journal of the Polish Physiological Society, Sep 1, 2009

Citation Hoy, Andrew J.; McLennan, Peter L.; and Peoples, Gregory E., 2009, The effect of vasocon... more Citation Hoy, Andrew J.; McLennan, Peter L.; and Peoples, Gregory E., 2009, The effect of vasoconstrictors on oxygen consumption in resting and contracting skeletal muscle of the autologous pump-perfused rat hindlimb, Journal of Physiology and Pharmacology, 60(3), 155-160.

P. L. (2003). The reduced effect of serotonin on oxygen consumption during muscle contraction in ... more P. L. (2003). The reduced effect of serotonin on oxygen consumption during muscle contraction in the autoperfused rat hindlimb. Exercise, Muscle & Metabolism (pp. 1-1). Melbourne: Deakin University.

Endocrinology, Apr 17, 2014

High-fat diet (HFD) feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/Agouti-rela... more High-fat diet (HFD) feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/Agouti-related peptide neurons. In the current study, we investigated the time course over which this occurs and the mechanisms responsible for ghrelin resistance. After 3 weeks of HFD feeding, neither peripheral nor central ghrelin increased food intake and or activated NPY neurons as demonstrated by a lack of Fos immunoreactivity or whole-cell patch-clamp electrophysiology. Pair-feeding studies that matched HFD calorie intake with chow calorie intake show that HFD exposure does not cause ghrelin resistance independent of body weight gain. We observed increased plasma leptin in mice fed a HFD for 3 weeks and show that leptin-deficient obese ob/ob mice are still ghrelin sensitive but become ghrelin resistant when central leptin is coadministered. Moreover, ob/ob mice fed a HFD for 3 weeks remain ghrelin sensitive, and the ability of ghrelin to induce action potential firing in NPY neurons was blocked by leptin. We also examined hypothalamic gliosis in mice fed a chow diet or HFD, as well as in ob/ob mice fed a chow diet or HFD and lean controls. HFD-fed mice exhibited increased glial fibrillary acidic protein-positive cells compared with chow-fed mice, suggesting that hypothalamic gliosis may underlie ghrelin resistance. However, we also observed an increase in hypothalamic gliosis in ob/ob mice fed a HFD compared with chow-fed ob/ob and lean control mice. Because ob/ob mice fed a HFD remain ghrelin sensitive, our results suggest that hypothalamic gliosis does not underlie ghrelin resistance. Further, pair-feeding a HFD to match the calorie intake of chow-fed controls did not increase body weight gain or cause central ghrelin resistance; thus, our evidence suggests that diet-induced hyperleptinemia, rather than diet-induced hypothalamic gliosis or HFD exposure, causes ghrelin resistance.

Bioorganic & Medicinal Chemistry, 2015

The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, pla... more The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9-13 and 16-20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50μM and 100μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes.

Molecular Cancer Therapeutics, 2015

Cell Metabolism, 2015

Liver steatosis is associated with the development of insulin resistance and the pathogenesis of ... more Liver steatosis is associated with the development of insulin resistance and the pathogenesis of type 2 diabetes. We tested the hypothesis that protein signals originating from steatotic hepatocytes communicate with other cells to modulate metabolic phenotypes. We show that the secreted factors from steatotic hepatocytes induce pro-inflammatory signaling and insulin resistance in cultured cells. Next, we identified 168 hepatokines, of which 32 were differentially secreted in steatotic versus non-steatotic hepatocytes. Targeted analysis showed that fetuin B was increased in humans with liver steatosis and patients with type 2 diabetes. Fetuin B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. Silencing of fetuin B in obese mice improved glucose tolerance. We conclude that the protein secretory profile of hepatocytes is altered with steatosis and is linked to inflammation and insulin resistance. Therefore, preventing steatosis may limit the development of dysregulated glucose metabolism in settings of overnutrition.

Journal of cell science, Jan 16, 2015

Tumor protein D52 (TPD52) is amplified/ over-expressed in cancers of diverse cellular origins. Al... more Tumor protein D52 (TPD52) is amplified/ over-expressed in cancers of diverse cellular origins. Altered cellular metabolism (including lipogenesis) is a hallmark of cancer development, and protein-protein associations between TPD52 and known regulators of lipid storage, and differential TPD52 expression in obese versus non-obese adipose tissue, suggest that TPD52 may regulate cellular lipid metabolism. We found increased lipid droplet numbers in stably TPD52-expressing BALB/c 3T3 cell lines, compared with control and TPD52L1-expressing cell lines. TPD52-expressing 3T3 cells showed increased fatty acid storage in triglyceride (from both de novo synthesis and uptake), and formed greater numbers of lipid droplets upon oleic acid supplementation than control cells. TPD52 co-localised with Golgi but not ER markers, and also showed partial co-localisation with Adrp-coated lipid droplets, with a proportion of TPD52 being detected in the lipid droplet fraction. Direct interactions between AD...

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2009

This study used a novel in vivo model to test the hypothesis that nutritive and non-nutritive blo... more 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 diminis...

Cancer & Metabolism, 2014

The Journal of Physiology, 2008

The Journal of Physiology The Journal of Physiology. Skip to main page content. ...

Microcirculation, 2013

Objective Oxygen delivery, underpinned by vascular tone, is the principle limiting factor in the ... more Objective Oxygen delivery, underpinned by vascular tone, is the principle limiting factor in the study of skeletal muscle physiology, particularly during muscle contraction. The aim of this study was to develop an autologous perfused rat hind limb preparation for the study of skeletal muscle contractile function.

Liver International, 2013

Endocrinology, 2011

Adipose triglyceride lipase (ATGL) null (Ϫ/Ϫ) mice store vast amounts of triacylglycerol in key g... more Adipose triglyceride lipase (ATGL) null (Ϫ/Ϫ) 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 ATGLϪ/Ϫ mice persist when challenged with a high-fat diet. ATGLϪ/Ϫ 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. ATGLϪ/Ϫ mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to prehigh-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 ATGLϪ/Ϫ 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 ATGLϪ/Ϫ mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity. (Endocrinology 152: 48 -58, 2011)

Diabetologia, 2011

Aims/hypothesis Hepatic steatosis is characterised by excessive triacylglycerol accumulation and ... more Aims/hypothesis 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. Methods Studies of fatty acid metabolism were conducted in primary hepatocytes isolated from wild-type and Atgl (also known as Pnpla2) −/− mice. An ATGL adenovirus was utilised to overproduce ATGL in the livers of obese insulinresistant C57Bl/6 mice (Ad-ATGL). Blood chemistry, hepatic lipid content and insulin sensitivity were assessed in mice. Results Triacylglycerol content was increased in Atgl −/− hepatocytes and was associated with increased fatty acid uptake and impaired fatty acid oxidation. ATGL adenovirus administration in obese mice increased the production of hepatic ATGL protein and reduced triacylglycerol, diacylglycerol and ceramide content in the liver. Overproduction of ATGL improved insulin signal transduction in the liver but did not affect fasting glycaemia or insulinaemia. Inflammatory signalling was not suppressed by ATGL overproduction. While ATGL overproduction increased plasma non-esterified fatty acids, neither lipid deposition nor insulin-stimulated glucose uptake were affected in skeletal muscle. Conclusions/interpretation Liver ATGL overproduction decreases hepatic steatosis and mildly enhances liver insulin sensitivity. These effects are not sufficient to improve fasting glycaemia or insulinaemia in rodent obesity.

AJP: Endocrinology and Metabolism, 2012

Watt MJ, Hoy AJ. Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intr... more Watt MJ, Hoy AJ. Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. 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 stored primarily 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 1) discuss 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 byproducts 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.