Adrian Cooper
Deakin University
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Featured researches published by Adrian Cooper.
PLOS ONE | 2014
Briana Spolding; Timothy Connor; Carrie Wittmer; Lelia L. F. de Abreu; Antony Kaspi; Mark Ziemann; Gunveen Kaur; Adrian Cooper; Shona Morrison; Scott Lee; Andrew J. Sinclair; Yann Gibert; James L. Trevaskis; Jonathon D. Roth; Assam El-Osta; Richard Standish; Ken Walder
Background and Aims A major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat). Methods P. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR. Results P. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export. Conclusions P. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients.
Diabetes | 2012
Nicky Konstantopoulos; Juan Carlos Molero; Sean L. McGee; Briana Spolding; Timothy Connor; Melissa de Vries; Stephen Wanyonyi; R. Fahey; Shona Morrison; Courtney Swinton; Sharon Jones; Adrian Cooper; Lucía García-Guerra; Victoria C. Foletta; Guy Krippner; Sofianos Andrikopoulos; Ken Walder
We previously used Gene Expression Signature technology to identify methazolamide (MTZ) and related compounds with insulin sensitizing activity in vitro. The effects of these compounds were investigated in diabetic db/db mice, insulin-resistant diet-induced obese (DIO) mice, and rats with streptozotocin (STZ)-induced diabetes. MTZ reduced fasting blood glucose and HbA1c levels in db/db mice, improved glucose tolerance in DIO mice, and enhanced the glucose-lowering effects of exogenous insulin administration in rats with STZ-induced diabetes. Hyperinsulinemic-euglycemic clamps in DIO mice revealed that MTZ increased glucose infusion rate and suppressed endogenous glucose production. Whole-body or cellular oxygen consumption rate was not altered, suggesting MTZ may inhibit glucose production by different mechanism(s) to metformin. In support of this, MTZ enhanced the glucose-lowering effects of metformin in db/db mice. MTZ is known to be a carbonic anhydrase inhibitor (CAI); however, CAIs acetazolamide, ethoxyzolamide, dichlorphenamide, chlorthalidone, and furosemide were not effective in vivo. Our results demonstrate that MTZ acts as an insulin sensitizer that suppresses hepatic glucose production in vivo. The antidiabetic effect of MTZ does not appear to be a function of its known activity as a CAI. The additive glucose-lowering effect of MTZ together with metformin highlights the potential utility for the management of type 2 diabetes.
Biochimica et Biophysica Acta | 2010
Juan Carlos Molero; Scott Lee; Ilit Leizerman; Ayelet Chajut; Adrian Cooper; Ken Walder
OBJECTIVE To examine the effects of rosiglitazone in intramyocellular lipid (IMCL) content in diabetic Psammomys obesus using novel electron microscopy technologies. BACKGROUND P. obesus is an unique polygenic model of obesity and type 2 diabetes. Male diabetic P. obesus were treated daily with 5 mg/Kg Rosiglitazone by oral gavage for 14 days. Data were compared with a group of age-matched diabetic P. obesus treated with saline vehicle. METHODS Assessment of insulin resistance and adiposity were determine before and after the treatment period by oral glucose tolerance test (oGTT) and dual energy X-ray absorptiometry (DEXA) analysis. We used a new scanning electron microscopy technology, (WETSEM) to investigate the effects of rosiglitazone administration on IMCL content, size and distribution in red gastrocnemius muscle. RESULTS Rosiglitazone treatment improved glucose tolerance in P. obesus with no difference in the overall body fat content although a significant reduction in subscapular fat mass was observed. Rosiglitazone changed the distribution of lipid droplet size in skeletal muscle. Treated animals tended to have smaller lipid droplets compared with saline-treated controls. CONCLUSIONS Since smaller IMCL droplets are associated with improvements in insulin sensitivity, we propose that this may be an important mechanism by which rosiglitazone affects glucose tolerance.
International Journal of Obesity | 2016
Ishant Khurana; Antony Kaspi; Mark Ziemann; T Block; Timothy Connor; Briana Spolding; Adrian Cooper; Paul Zimmet; Assam El-Osta; Ken Walder
Background/Objective:The rising incidence of obesity is a major public health issue worldwide. Recent human and animal studies suggest that parental diet can influence fetal development and is implicated with risk of obesity and type 2 diabetes in offspring. The hypothalamus is central to body energy homoeostasis and appetite by controlling endocrine signals. We hypothesise that offspring susceptibility to obesity is programmed in the hypothalamus in utero and mediated by changes to DNA methylation, which persist to adulthood. We investigated hypothalamic genome-wide DNA methylation in Psammomys obesus diet during pregnancy to the offspring’s risk of obesity.Methods:Using methyl-CpG binding domain capture and deep sequencing (MBD-seq), we examined the hypothalamus of offspring exposed to a low-fat diet and standard chow diet during the gestation and lactation period.Results:Offspring exposed to a low-fat parental diet were more obese and had increased circulating insulin and glucose levels. Methylome profiling identified 1447 genomic regions of differential methylation between offspring of parents fed a low-fat diet compared with parents on standard chow diet. Pathway analysis shows novel DNA methylation changes of hypothalamic genes associated with neurological function, nutrient sensing, appetite and energy balance. Differential DNA methylation corresponded to changes in hypothalamic gene expression of Tas1r1 and Abcc8 in the offspring exposed to low-fat parental diet.Conclusion:Subject to parental low-fat diet, we observe DNA methylation changes of genes associated with obesity in offspring.
The FASEB Journal | 2017
Simon T. Bond; Kirsten F. Howlett; Greg M. Kowalski; Shaun Mason; Timothy Connor; Adrian Cooper; Victor A. Streltsov; Clinton R. Bruce; Ken Walder; Sean L. McGee
Reciprocal regulation of hepatic glycolysis and gluconeogenesis contributes to systemic metabolic homeostasis. Recent evidence from lower order organisms has found that reversible post‐translational modification of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH), particularly acetylation, contributes to the reciprocal regulation of glycolysis/gluconeogenesis. However, whether this occurs in mammalian hepatocytes in vitro or in vivo is unknown. Several proteomics studies have identified 4 lysine residues in critical regions of mammalian GAPDH that are altered by multiple post‐translational modifications. In FAO hepatoma cells, mutation of all 4 lysine residues (4K‐R GAPDH) to mimic their unmodified state reduced GAPDH glycolytic activity and glycolytic flux and increased gluconeogenic GAPDH activity and glucose production. Hepatic expression of 4K‐R GAPDH in mice increased GAPDH gluconeogenic activity and the contribution of gluconeogenesis to endogenous glucose production in the unfed state. Consistent with the increased reliance on the energy‐consuming gluconeogenic pathway, plasma free fatty acids and ketones were elevated in mice expressing 4K‐R GAPDH, suggesting enhanced lipolysis and hepatic fatty acid oxidation. In normal mice, food withholding and refeeding, as well as hormonal regulators of reciprocal glycolysis/gluconeogenesis, such as insulin, glucagon, and norepinephrine, had no effect on global GAPDH acetylation. However, GAPDH acetylation was reduced in obese and type 2 diabetic db/db mice. These findings show that post‐translational modification of GAPDH lysine residues regulates hepatic and systemic metabolism, revealing an unappreciated role for hepatic GAPDH in substrate selection and utilization.—Bond, S. T., Howlett, K. F., Kowalski, G. M., Mason, S., Connor, T., Cooper, A., Streltsov, V., Bruce, C. R., Walder, K. R., McGee, S. L. Lysine post‐translational modification of glyceraldehyde‐3‐phosphate dehydrogenase regulates hepatic and systemic metabolism. FASEB J. 31, 2592–2602 (2017). www.fasebj.org
Epigenetics | 2014
Anthony Kaspi; Mark Ziemann; Samuel T. Keating; Ishant Khurana; Timothy Connor; Briana Spolding; Adrian Cooper; Ross Lazarus; Ken Walder; Paul Zimmet; Assam El-Osta
Current computational methods used to analyze changes in DNA methylation and chromatin modification rely on sequenced genomes. Here we describe a pipeline for the detection of these changes from short-read sequence data that does not require a reference genome. Open source software packages were used for sequence assembly, alignment, and measurement of differential enrichment. The method was evaluated by comparing results with reference-based results showing a strong correlation between chromatin modification and gene expression. We then used our de novo sequence assembly to build the DNA methylation profile for the non-referenced Psammomys obesus genome. The pipeline described uses open source software for fast annotation and visualization of unreferenced genomic regions from short-read data.
International Diabetes Federation. Congress (18th : 2003 : Paris, France) | 2003
James L. Trevaskis; Janine McMillan; Scott Lee; Adrian Cooper; Ryan Webb; Kate S. Elliott; Ken Walder; Gregory Collier
High prevalence of foot ulceration in the Balkan region a multicenter study from the BALKANDIAB network. C. N. Manes1, C. Ionescu-Tirgoviste2, L. Koeva3, D. Koev4, F. Agaci5, P. Djordjevic6, M. Bogoev7; 1Diabetes Unit, „Papageorgiou“ Gen. Hospital, Thessaloniki, Greece, 2N. Paulescu, Bucharest, Romania, 3University of Varna, Varna, Bulgaria, 4Bulgarian Society of Endocrinology, Sofia, Bulgaria, 5“Mother Teresa“, University Hospital Center, Tirana, Albania, 6Diabetes Unit, Institute of Endocrinology, Belgrade, Yugoslavia, 7Clinic of Endocrinology, Skopje, The former Yugoslav Republic of Macedonia.
Diabetes | 2006
Juan Carlos Molero; Samuel G. Waring; Adrian Cooper; Nigel Turner; Ross Laybutt; Gregory J. Cooney; David E. James
Endocrinology | 2005
James L. Trevaskis; Ken Walder; Victoria C. Foletta; Lyndal Kerr-Bayles; Janine McMillan; Adrian Cooper; Scott Lee; Kristy Bolton; Matthew Prior; R. Fahey; K. Whitecross; Gregory J. Morton; Michael W. Schwartz; Greg R. Collier
Pathology | 2017
Ishant Khurana; Antony Kaspi; Mark Ziemann; T. Block; Timothy Connor; Briana Spolding; Adrian Cooper; Paul Zimmet; Assam El-Osta; Ken Walder