2019

Role of branched-chain amino acid-catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis. Biswas D, Duffley L, Pulinilkunnil T. FASEB. 2019 May 14:fj201802842RR. doi: 10.1096/fj.201802842RR.

Beyond their contribution as fundamental building blocks of life, branched-chain amino acids (BCAAs) play a critical role in physiologic and pathologic processes. Importantly, BCAAs are associated with insulin resistance, obesity, cardiovascular disease, and genetic disorders. However, several metabolome-wide studies in Read More

Impact of Obesity on Postoperative Outcomes following cardiac Surgery (The OPOS study): rationale and design of an investigator-initiated prospective study. Aguiar C, MacLeod J, Yip A, Melville S, Légaré JF, Pulinilkunnil T, Kienesberger P, Brunt K, Hassan A. BMJ Open. 2019 Mar 3;9(3):e023418. doi: 10.1136/bmjopen-2018-023418.

INTRODUCTION: Increasing levels of obesity worldwide have led to a rise in the prevalence of obesity-related complications including cardiovascular risk factors such as diabetes, hypertension and dyslipidaemia. Healthcare providers believe that overweight and obese cardiac surgery patients are more likely Read More

2018

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism. D’Souza K, Nzirorera C, Cowie AM, Varghese GP, Trivedi P, Eichmann TO, Biswas D, Touaibia M, Morris AJ, Aidinis V, Kane DA, Pulinilkunnil T, Kienesberger PC. J Lipid Res. 2018 Oct;59(10):1805-1817. doi: 10.1194/jlr.M082008.

Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in Read More

Lysophosphatidic acid signaling in obesity and insulin resistance. D’Souza K, Paramel GV, Kienesberger PC. Nutrients. 2018 Mar 23;10(4). pii: E399.

Although simple in structure, lysophosphatidic acid (LPA) is a potent bioactive lipid that profoundly influences cellular signaling and function upon binding to G protein-coupled receptors (LPA1-6). The majority of circulating LPA is produced by the secreted enzyme autotaxin (ATX). Alterations Read More

2017

Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans. Brown A, Hossain I, Perez LJ, Nzirorera C, Tozer K, D’Souza K, Trivedi PC, Aguiar C, Yip AM, Shea J, Brunt KR, Legare JF, Hassan A, Pulinilkunnil T, Kienesberger PC. PLoS One. 2017 Dec 13;12(12):e0189402.

BACKGROUND: Lysophosphatidic acid (LPA) receptor signaling has been implicated in cardiovascular and obesity-related metabolic disease. However, the distribution and regulation of LPA receptors in the myocardium and adipose tissue remain unclear. OBJECTIVES: This study aimed to characterize the mRNA expression Read More

Inhibition of ADAM17/TACE activity by zinc-chelating rye secalin-derived tripeptides and analogues. Udechukwu MC, Tsopmo A, Mawhinney H, He R, Kienesberger PC, Udenigwe C. RSC Adv. 2017 7, 26361-26369.

A disintegrin and metalloproteinase 17” (ADAM17), or tumour necrosis factor (TNF)-α converting enzyme, is an upstream target for mitigating TNF-α-mediated inflammation. ADAM17 can be inhibited by chelation of its catalytic site zinc cofactor, which is required for substrate catalysis and Read More

Validation of optimal reference genes for quantitative real time PCR in muscle and adipose tissue for obesity and diabetes research. Perez LJ, Rios L, Trivedi P, D’Souza K, Cowie A, Nzirorera C, Webster D, Brunt K, Legare JF, Hassan A, Kienesberger PC, Pulinilkunnil T. Sci Rep. 2017 Jun 15;7(1):3612.

The global incidence of obesity has led to an increasing need for understanding the molecular mechanisms that drive this epidemic and its comorbidities. Quantitative real-time RT-PCR (RT-qPCR) is the most reliable and widely used method for gene expression analysis. The Read More

Changes in Circulating Monocyte Subsets (CD16 Expression) and Neutrophil-to-Lymphocyte Ratio Observed in Patients Undergoing Cardiac Surgery. Gawdat K, Legere S, Wong C, Myers T, Marshall JS, Hassan A, Brunt KR, Kienesberger PC, Pulinilkunnil T, Legare JF. Front Cardiovasc Med. 2017 Mar 15;4:12.

BACKGROUND: The characteristics of circulating inflammatory cells (leukocytes) in patients undergoing heart surgery remains poorly understood. Recently, neutrophil-to-lymphocyte ratio (NLR) and specific monocyte subsets (based on CD14/CD16 expression) have been suggested as markers of inflammation and predictors of outcomes. The Read More

Dieldrin augments mTOR signaling and inhibits lysosomal acidification in the adult zebrafish heart (Danio rerio). Slade L, Cowie A, Martyniuk CJ, Kienesberger PC, Pulinilkunnil T. J Pharmacol Exp Ther. 2017 Jun;361(3):375-385.

Dieldrin is a legacy organochlorine pesticide that is persistent in the environment, despite being discontinued from use in North America since the 1970s. Some epidemiological studies suggest that exposure to dieldrin is associated with increased risks of neurodegenerative disease and Read More

Autotaxin is regulated by glucose and insulin in adipocytes. D’Souza K, Kane DA, Touaibia M, Kershaw EE, Pulinilkunnil T, Kienesberger PC. Endocrinology. 2017 Apr 1;158(4):791-803.

Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid. Despite recent studies implicating adipose-derived ATX in metabolic disorders including obesity and insulin resistance, the nutritional and hormonal regulation of ATX in adipocytes remains unclear. The current study Read More

The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation. Slade L, Pulinilkunnil T. Mol Cancer Res. 2017 Dec;15(12):1637-1643.

The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of transcription factors is emerging as global regulators of cancer cell survival and energy metabolism, both through the promotion of lysosomal genes as well as newly characterized targets, such as oxidative metabolism Read More

Cardiac complications of congenital disorders of glycosylation (CDG): a systematic review of the literature. Marques-da-Silva D, Francisco R, Webster D, Dos Reis Ferreira V, Jaeken J, Pulinilkunnil T. J Inherit Metab Dis. 2017 Sep;40(5):657-672.

Congenital disorders of glycosylation (CDG) areinborn errors of metabolism due to protein and lipidhypoglycosylation. This rapidly growing family of geneticdiseases comprises 103 CDG types, with a broad phenotypicdiversity ranging from mild to severe poly-organ -system dys-function. This literature review summarizes Read More

Heparanase overexpression induces glucagon resistance and protects animals from chemically-induced diabetes. Zhang D, Wang F, Lal N, Chiu AP, Wan A, Jia J, Bierende D, Flibotte S, Sinha S, Asadi A, Hu X, Taghizadeh F, Pulinilkunnil T, Nislow C, Vlodavsky I, Johnson JD, Kieffer TJ, Hussein B, Rodrigues B. Diabetes. 2017 Jan;66(1):45-57.

Heparanase, a protein with enzymatic and nonenzymatic properties, contributes toward disease progression and prevention. In the current study, a fortuitous observation in transgenic mice globally overexpressing heparanase (hep-tg) was the discovery of improved glucose homeostasis. We examined the mechanisms that Read More

2016

Doxorubicin impairs cardiomyocyte viability by suppressing transcription factor EB expression and disrupting autophagy. Bartlett JJ, Trivedi PC, Yeung P, Kienesberger PC, Pulinilkunnil T. Biochem J. 2016 Nov 1;473(21):3769-3789.

Doxorubicin (DOX)-induced cardiotoxicity has been a well-known phenomenon to clinicians and scientists for decades; however, molecular mechanisms underlying DOX cardiotoxicity are still being uncovered. Although the majority of prior research have implicated nuclear and mitochondrial events to be an important Read More

Glucolipotoxicity diminishes cardiomyocyte TFEB and inhibits lysosomal autophagy during obesity and diabetes. Trivedi PC, Bartlett JJ, Perez LJ, Brunt KR, Legare JF, Hassan A, Kienesberger PC, Pulinilkunnil T. Biochim Biophys Acta. 2016 Dec;1861(12 Pt A):1893-1910.

Impaired cardiac metabolism in the obese and diabetic heart leads to glucolipotoxicity and ensuing cardiomyopathy. Glucolipotoxicity causes cardiomyocyte injury by increasing energy insufficiency, impairing proteasomal-mediated protein degradation and inducing apoptosis. Proteasome-evading proteins are degraded by autophagy in the lysosome, whose Read More

Lipid metabolism and signaling in cardiac lipotoxicity. D’Souza K, Nzirorera C, Kienesberger PC. Biochim Biophys Acta. 2016 Oct;1861(10):1513-24.

The heart balances uptake, metabolism and oxidation of fatty acids (FAs) to maintain ATP production, membrane biosynthesis and lipid signaling. Under conditions where FA uptake outpaces FA oxidation and FA sequestration as triacylglycerols in lipid droplets, toxic FA metabolites such Read More

New Atglistatin closely related analogues: synthesis and structure-activity relationship towards adipose triglyceride lipase inhibition. Roy PP, D’Souza K, Cuperlovic-Culf M, Kienesberger PC, Touaibia M. Eur J Med Chem. 2016 Aug 8;118:290-8.

Adipose Triglyceride Lipase (ATGL) performs the first and rate-limiting step in lipolysis by hydrolyzing triacylglycerols stored in lipid droplets to diacylglycerols. By mediating lipolysis in adipose and non-adipose tissues, ATGL is a major regulator of overall energy metabolism and plasma Read More

Myocardial Insulin Signaling and Autophagy. Bartlett J, Trivedi P, Rodrigues B, Pulinilkunnil T. Autophagy and Cardiometabolic Diseases 1st Edition From Molecular Mechanisms to Translational Medicine. eBook ISBN: 9780128054420

Autophagy and Cardiometabolic Diseases: From Moleculer Mechanisms to Translational Medicine covers the science of autophagy in relation to cardiometabolic diseases and the future therapeutic potentials of autophagy regulation in these processes. Processes are not described in isolation, but in concert with Read More

2015

Serum Autotaxin/ENPP2 Correlates with Insulin Resistance in Older Obese Humans. Reeves VL, Trybula JS, Wills RC, Goodpaster BH, Dubé JJ, Kienesberger PC, Kershaw EE. Obesity (Silver Spring). 2015 Dec;23(12):2371-6.

OBJECTIVE: Autotaxin (ATX) is an adipocyte-derived lysophospholipase D that generates the lipid signaling molecule lysophosphatidic acid (LPA). The ATX/LPA pathway in adipose tissue has recently been implicated in obesity and insulin resistance in animal models, but the role of circulating Read More

Serum autotaxin is independently associated with hepatic steatosis in severely obese women. Rachakonda VP, Reeves VL, Aljammal J, Wills RC, Trybula JS, DeLany JP, Kienesberger PC, Kershaw EE. Obesity (Silver Spring). 2015 May;23(5):965-72.

OBJECTIVE: Autotaxin (ATX) is an adipocyte-derived lysophospholipase that generates the lipid signaling molecule lysophosphatidic acid (LPA). The aim of this study was to determine the relationship between serum ATX and nonalcoholic fatty liver disease (NAFLD) in females with obesity. METHODS: Read More

Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice. Resistance and Inflammation in Male Mice. Schoiswohl G, Stefanovic-Racic M, Menke MN, Wills RC, Surlow BA, Basantani MK, Sitnick MT, Cai L, Yazbeck CF, Stolz DB, Pulinilkunnil T, O’Doherty RM, Kershaw EE. Endocrinology. 2015 Oct;156(10):3610-24.

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis Read More

Skeletal muscle AMPK and ACC2 S212 phosphorylation is not required for the control of fatty acid oxidation during exercise. O’Neill HM, Lally JS, Galic S, Pulinilkunnil T, Ford RJ, Dyck JR, van Denderen BJ, Kemp BE, Steinberg GR. Physiol Rep. 2015 Jul;3(7). pii: e12444.

During submaximal exercise fatty acids are a predominant energy source for muscle contractions. An important regulator of fatty acid oxidation is acetyl-CoA carboxylase (ACC), which exists as two isoforms (ACC1 and ACC2) with ACC2 predominating in skeletal muscle. Both ACC Read More

Adipose triglyceride lipase (ATGL) deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice. Dubé JJ, Sitnick MT, Schoiswohl G, Wills RC, Basantani MK, Cai L, Pulinilkunnil T, Kershaw EE. Am J Physiol Endocrinol Metab. 2015 May 15;308(10):E879-90.

Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triacylglycerol hydrolysis in virtually all cells, including adipocytes and skeletal myocytes, and hence, plays a critical role in mobilizing fatty acids. Global ATGL deficiency promotes skeletal myopathy and exercise intolerance in Read More

Insulin Signaling in Cardiac Health and Disease. Bartlett J, Trivedi P, Pulinilkunnil T. Chapter 12. In: Endocrinology of the Heart in Health and Disease. Jonathan Cummings Schisler, Charles Lang, Monte Willis (Eds.). Elsevier Press Publishers, 317-347.

Endocrinology of the Heart in Health and Disease: Integrated, Cellular, and Molecular Endocrinology of the Heart covers the traditional concepts of cardio-endocrinology, the role of the various hormone systems, both in health and disease, therapeutic implications, and other recent advances in Read More

Myocardial metabolic abnormalities and cardiac dysfunction. Kienesberger PC. Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Springer, Part II, Chapter 17, p. 325-341.

To sustain contractile function, the myocardium has a very high and continuous demand for ATP, which it generates from a variety of carbon sources, including fatty acids, glucose, ketone bodies, pyruvate, and lactate. In the healthy adult heart, most of Read More

2014

AMPK-Dependent Inhibitory Phosphorylation of ACC is not Essential for Maintaining Myocardial Fatty Acid Oxidation. Zordoky BN, Nagendran J, Pulinilkunnil T, Kienesberger PC, Masson G, Waller TJ, Kemp BE, Steinberg GR, Dyck JR. Circ Res. 2014 Aug 15;115(5):518-24.

Rationale: The energy sensor AMP-activated protein kinases (AMPK) is thought to play an important role in regulating myocardial fatty acid oxidation (FAO) via its phosphorylation and inactivation of acetyl coenzyme A carboxylase (ACC). However, studies supporting this have not directly assessed Read More

Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, Pirinen E, Pulinilkunnil TC, Gong F, Wang YC, Cen Y, Sauve AA, Asara JM, Peroni OD, Monia BP, Bhanot S, Alhonen L, Puigserver P, Kahn BB. Nature. 2014 Apr 10;508(7495):258-62.

In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes1. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity2. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing Read More

The role of ubiquitin ligases in cardiac disease. Willis MS, Bevilacqua A, Pulinilkunnil T, Kienesberger P, Tannu M, Patterson C. J Mol Cell Cardiol. 2014 Jun;71:43-53.

Rigorous surveillance of protein quality control is essential for the maintenance of normal cardiac function, while the dysregulation of protein turnover is present in a diverse array of common cardiac diseases. Central to the protein quality control found in all Read More

The Pathophysiology of Cardiac Hypertrophy and Heart Failure. Stansfield WE, Ranek M, Pendse A, Schisler JC, Wang S, Pulinilkunnil T, Willis MS. Cellular and Molecular Pathobiology of Cardiovascular Disease, Chapter 4, 2014, Pages 51-78

Left ventricular hypertrophy (LVH) is one of the most common cardiovascular diseases; the estimated prevalence is 20{8617e24ab0b76aabcd10cf8004a7bdc562123dc1ea8adc37299158a7c05423e6} in the general population. In spite of being one of the greatest independent risk factors for cardiovascular morbidity and mortality, it remains essentially Read More

2013

Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery. Nagendran J, Pulinilkunnil T, Kienesberger PC, Sung MM, Fung D, Febbraio M, Dyck JR. J Mol Cell Cardiol. 2013 Oct;63:180-8.

Abstract Although pre-clinical evidence has suggested that partial inhibition of myocardial fatty acid oxidation (FAO) and subsequent switch to greater glucose oxidation for ATP production can prevent ischemia/reperfusion injury, controversy about this approach persists. For example, mice with germline deletion Read More

Cardiac-specific adipose triglyceride lipase overexpression protects from cardiac steatosis and dilated cardiomyopathy following diet-induced obesity. Pulinilkunnil T, Kienesberger PC, Nagendran J, Sharma N, Young ME, Dyck JR. Int J Obes (Lond). 2014 Feb;38(2):205-15.

BACKGROUND: Although obesity increases the risk of developing cardiomyopathy, the mechanisms underlying the development of this cardiomyopathy are incompletely understood. As obesity is also associated with increased intramyocardial triacylglycerol (TAG) deposition, also referred to as cardiac steatosis, we hypothesized that alterations in myocardial TAG metabolism and excess TAG accumulation Read More

Skeletal muscle triacylglycerol hydrolysis does not influence metabolic complications of obesity. Sitnick MT, Basantani MK, Cai L, Schoiswohl G, Yazbeck CF, Distefano G, Ritov V, DeLany JP, Schreiber R, Stolz DB, Gardner NP, Kienesberger PC, Pulinilkunnil T, Zechner R, Goodpaster BH, Coen P, Kershaw EE. Diabetes. 2013 Oct;62(10):3350-61.

Intramyocellular triacylglycerol (IMTG) accumulation is highly associated with insulin resistance and metabolic complications of obesity (lipotoxicity), whereas comparable IMTG accumulation in endurance-trained athletes is associated with insulin sensitivity (the athlete's paradox). Despite these findings, it remains unclear whether changes in IMTG accumulation Read More

Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism. Breckenridge RA, Piotrowska I, Ng KE, Ragan TJ, West JA, Kotecha S, Towers N, Bennett M, Kienesberger PC, Smolenski RT, Siddall HK, Offer JL, Mocanu MM, Yelon DM, Dyck JR, Griffin JL, Abramov AY, Gould AP, Mohun TJ. PLoS Biol. 2013 Sep;11(9):e1001666.

Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, Read More

Cardiomyocyte specific adipose triglyceride lipase overexpression prevents doxorubicin induced cardiac dysfunction in female mice. Nagendran J, Kienesberger PC, Pulinilkunnil T, Zordoky BN, Sung MM, Kim T, Young ME, Dyck JR. Heart. 2013 Jul;99(14):1041-7.

OBJECTIVES: Anthracyclines such as doxorubicin are an effective class of antineoplastic agents. Despite its efficacy in the treatment of a variety of cancers, the clinical use of doxorubicin is limited by cardiac side effects. While it has been suggested that doxorubicin alters myocardial fatty acid metabolism, it is Read More

Myocardial adipose triglyceride lipase overexpression protects diabetic mice from the development of lipotoxic cardiomyopathy. Pulinilkunnil T, Kienesberger PC, Nagendran J, Waller TJ, Young ME, Kershaw EE, Korbutt G, Haemmerle G, Zechner R, Dyck JR. Diabetes. 2013 May;62(5):1464-77.

Although diabetic cardiomyopathy is associated with enhanced intramyocardial triacylglycerol (TAG) levels, the role of TAG catabolizing enzymes in this process is unclear. Because the TAG hydrolase, adipose triglyceride lipase (ATGL), regulates baseline cardiac metabolism and function, we examined whether alterations in cardiomyocyte ATGL impact cardiac function during Read More

Myocardial triacylglycerol metabolism. Kienesberger PC, Pulinilkunnil T, Nagendran J, Dyck JR. J Mol Cell Cardiol. 2013 Feb;55:101-10.

Myocardial triacylglycerol (TAG) constitutes a highly dynamic fatty acid (FA) storage pool that can be used for an energy reserve in the cardiomyocyte. However, derangements in myocardial TAG metabolism and accumulation are commonly associated with cardiac disease, suggesting an important Read More

Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation. Kienesberger PC, Pulinilkunnil T, Nagendran J, Young ME, Bogner-Strauss JG, Hackl H, Khadour R, Heydari E, Haemmerle G, Zechner R, Kershaw EE, Dyck JR. Cardiovasc Res. 2013 Aug 1;99(3):442-51.

AIMS: While chronic alterations in cardiac triacylglycerol (TAG) metabolism and accumulation are associated with cardiomyopathy, it is unclear whether TAG catabolizing enzymes such as adipose triglyceride lipase (ATGL) play a role in acquired cardiomyopathies. Importantly, germline deletion of ATGL leads to marked cardiac steatosis and heart failure in Read More

Enhanced recovery from ischemia-reperfusion injury in PI3Kα dominant negative hearts: investigating the role of alternate PI3K isoforms, increased glucose oxidation and MAPK signaling. McLean BA, Kienesberger PC, Wang W, Masson G, Zhabyeyev P, Dyck JR, Oudit GY. J Mol Cell Cardiol. 2013 Jan;54:9-18.

Classical ischemia–reperfusion (IR) preconditioning relies on phosphatidylinositol 3-kinase (PI3K) for protective signaling. Surprisingly, inhibition of PI3Kα activity using a dominant negative (DN) strategy protected the murine heart from IR injury. It has been proposed that increased signaling through PI3Kγ may Read More

Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury. Lou PH, Zhang L, Lucchinetti E, Heck M, Affolter A, Gandhi M, Kienesberger PC, Hersberger M, Clanachan AS, Zaugg M. Cardiovasc Res. 2013 Feb 1;97(2):251-61.

Aims Infarct-remodelled hearts are less amenable to protection against ischaemia/reperfusion. Understanding preservation of energy metabolism in diseased vs. healthy hearts may help to develop anti-ischaemic strategies effective also in jeopardized myocardium. Methods and results Isolated infarct-remodelled/sham Sprague–Dawley rat hearts were Read More

Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O’Neill HM, Ford RJ, Palanivel R, O’Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JR, van Denderen BJ, Kemp BE, Steinberg GR. Nat Med. 2013 Dec;19(12):1649-54.

The obesity epidemic has led to an increased incidence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes. AMP-activated protein kinase (Ampk) regulates energy homeostasis and is activated by cellular stress, hormones and the widely prescribed type 2 diabetes drug metformin. Ampk Read More