Publications by authors named "John R Ussher"

75 Publications

Cardiovascular outcome trials in Type 2 diabetes: food for thought.

Future Cardiol 2021 Feb 5. Epub 2021 Feb 5.

Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2H1, Canada.

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http://dx.doi.org/10.2217/fca-2021-0004DOI Listing
February 2021

The Impact of Antidiabetic Therapies on Diastolic Dysfunction and Diabetic Cardiomyopathy.

Front Physiol 2020 7;11:603247. Epub 2020 Dec 7.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.

Diabetic cardiomyopathy is more prevalent in people with type 2 diabetes mellitus (T2DM) than previously recognized, while often being characterized by diastolic dysfunction in the absence of systolic dysfunction. This likely contributes to why heart failure with preserved ejection fraction is enriched in people with T2DM vs. heart failure with reduced ejection fraction. Due to revised mandates from major health regulatory agencies, all therapies being developed for the treatment of T2DM must now undergo rigorous assessment of their cardiovascular risk profiles prior to approval. As such, we now have data from tens of thousands of subjects with T2DM demonstrating the impact of major therapies including the sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors on cardiovascular outcomes. Evidence to date suggests that both SGLT2 inhibitors and GLP-1R agonists improve cardiovascular outcomes, whereas DPP-4 inhibitors appear to be cardiovascular neutral, though evidence is lacking to determine the overall utility of these therapies on diastolic dysfunction or diabetic cardiomyopathy in subjects with T2DM. We herein will review the overall impact SLGT2 inhibitors, GLP-1R agonists, and DPP-4 inhibitors have on major parameters of diastolic function, while also highlighting the potential mechanisms of action responsible. A more complete understanding of how these therapies influence diastolic dysfunction will undoubtedly play a major role in how we manage cardiovascular disease in subjects with T2DM.
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http://dx.doi.org/10.3389/fphys.2020.603247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750477PMC
December 2020

SP1-independent inhibition of FOXM1 by modified thiazolidinediones.

Eur J Med Chem 2021 Jan 10;209:112902. Epub 2020 Oct 10.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. Electronic address:

This research article describes an approach to modify the thiazolidinedione scaffold to produce test drugs capable of binding to, and inhibit, the in vitro transcriptional activity of the oncogenic protein FOXM1. This approach allowed us to obtain FOXM1 inhibitors that bind directly to the FOXM1-DNA binding domain without targeting the expression levels of Sp1, an upstream transcription factor protein known to activate the expression of FOXM1. Briefly, we modified the chemical structure of the thiazolidinedione scaffold present in anti-diabetic medications such as pioglitazone, rosiglitazone and the former anti-diabetic drug troglitazone, because these drugs have been reported to exert inhibition of FOXM1 but hit other targets as well. After the chemical synthesis of 11 derivatives possessing a modified thiazolidinedione moiety, we screened all test compounds using in vitro protocols to measure their ability to (a) dissociate a FOXM1-DNA complex (EMSA assay); (b) decrease the expression of FOXM1 in triple negative-breast cancer cells (WB assay); (c) downregulate the expression of FOXM1 downstream targets (luciferase reporter assays and qPCR); and inhibit the formation of colonies of MDA-MB-231 cancer cells (colony formation assay). We also identified a potential binding mode associated with these compounds in which compound TFI-10, one of the most active molecules, exerts binding interactions with Arg289, Trp308, and His287. Unlike the parent drug, troglitazone, compound TFI-10 does not target the in vitro expression of Sp1, suggesting that it is possible to design FOXM1 inhibitors with a better selectivity profile.
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http://dx.doi.org/10.1016/j.ejmech.2020.112902DOI Listing
January 2021

Myocardial Energy Metabolism in Non-ischemic Cardiomyopathy.

Front Physiol 2020 16;11:570421. Epub 2020 Sep 16.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.

As the most metabolically demanding organ in the body, the heart must generate massive amounts of energy adenosine triphosphate (ATP) from the oxidation of fatty acids, carbohydrates and other fuels (e.g., amino acids, ketone bodies), in order to sustain constant contractile function. While the healthy mature heart acts omnivorously and is highly flexible in its ability to utilize the numerous fuel sources delivered to it through its coronary circulation, the heart's ability to produce ATP from these fuel sources becomes perturbed in numerous cardiovascular disorders. This includes ischemic heart disease and myocardial infarction, as well as in various cardiomyopathies that often precede the development of overt heart failure. We herein will provide an overview of myocardial energy metabolism in the healthy heart, while describing the numerous perturbations that take place in various non-ischemic cardiomyopathies such as hypertrophic cardiomyopathy, diabetic cardiomyopathy, arrhythmogenic cardiomyopathy, and the cardiomyopathy associated with the rare genetic disease, Barth Syndrome. Based on preclinical evidence where optimizing myocardial energy metabolism has been shown to attenuate cardiac dysfunction, we will discuss the feasibility of myocardial energetics optimization as an approach to treat the cardiac pathology associated with these various non-ischemic cardiomyopathies.
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http://dx.doi.org/10.3389/fphys.2020.570421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526697PMC
September 2020

The GLP-1 Receptor Agonist Liraglutide Increases Myocardial Glucose Oxidation Rates via Indirect Mechanisms and Mitigates Experimental Diabetic Cardiomyopathy.

Can J Cardiol 2021 Jan 8;37(1):140-150. Epub 2020 Mar 8.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background: Type 2 diabetes (T2D) increases risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor to augment insulin secretion, reduces cardiovascular-related death in people with T2D, though it remains unknown how liraglutide produces these actions. Notably, the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, making it likely that ventricular myocardium-independent actions are involved. We hypothesized that augmented insulin secretion may explain how liraglutide indirectly mediates cardioprotection, which thereby increases myocardial glucose oxidation.

Methods: C57BL/6J male mice were fed either a low-fat diet (lean) or were subjected to experimental T2D and treated with either saline or liraglutide 3× over a 24-hour period. Mice were subsequently euthanized and had their hearts perfused in the working mode to assess energy metabolism. A separate cohort of mice with T2D were treated with either vehicle control or liraglutide for 2 weeks for the assessment of cardiac function via ultrasound echocardiography.

Results: Treatment of lean mice with liraglutide increased myocardial glucose oxidation without affecting glycolysis. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with T2D and associated with increased circulating insulin levels. Furthermore, liraglutide treatment alleviated diastolic dysfunction in mice with T2D, which was associated with enhanced pyruvate dehydrogenase activity, the rate-limiting enzyme of glucose oxidation.

Conclusions: Our data demonstrate that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may contribute to how liraglutide improves cardiovascular outcomes in people with T2D.
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http://dx.doi.org/10.1016/j.cjca.2020.02.098DOI Listing
January 2021

Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure.

Circ Heart Fail 2020 06 4;13(6):e006573. Epub 2020 Jun 4.

Cardiovascular Research Centre (N.J.B., S.S., S.T., M.F., R.A.B., J.L.L., D.B., D.Y.V., M.A.S., A.S.A., Z.H.M., J.M.S., J.R.U., J.R.B.D.), University of Alberta, Edmonton, Canada.

Background: Previous studies have shown beneficial effects of acute infusion of the primary ketone body, β-hydroxybutyrate, in heart failure (HF). However, whether chronic elevations in circulating ketones are beneficial remains unknown.

Methods: To chronically elevate circulating ketones in mice, we deleted the expression of the ketolytic, rate-limiting-enzyme, SCOT (succinyl-CoA:3-ketoacid-CoA transferase 1; encoded by ), in skeletal muscle. Tamoxifen-inducible skeletal muscle-specific knockout (n=32) mice and littermate controls (wild type; WT; n=35) were subjected to transverse aortic constriction (TAC) surgery to induce HF.

Results: Deletion of SCOT in skeletal, but not cardiac muscle resulted in elevated concentrations of fasted circulating β-hydroxybutyrate in knockout mice compared with WT mice (=0.030). Five weeks following TAC, WT mice progressed to HF, whereas knockout mice with elevated fasting circulating ketones were largely protected from the TAC-induced effects observed in WT mice (ejection fraction, =0.011; mitral E/A, =0.012). Furthermore, knockout mice with TAC had attenuated expression of markers of sterile inflammation and macrophage infiltration, which were otherwise elevated in WT mice subjected to TAC. Lastly, addition of β-hydroxybutyrate to isolated hearts was associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3)-inflammasome activation, which has been previously shown to play a role in contributing to HF-induced cardiac inflammation.

Conclusions: These data show that chronic elevation of circulating ketones protects against the development of HF that is associated with the ability of β-hydroxybutyrate to directly reduce inflammation. These beneficial effects of ketones were associated with reduced cardiac NLRP3 inflammasome activation, suggesting that ketones may modulate cardiac inflammation via this mechanism.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006573DOI Listing
June 2020

Ketones can become the major fuel source for the heart but do not increase cardiac efficiency.

Cardiovasc Res 2020 May 13. Epub 2020 May 13.

Cardiovascular Research Centre Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Aims: Ketones have been proposed to be a "thrifty" fuel for the heart and increasing cardiac ketone oxidation can be cardioprotective. However, it is unclear how much ketone oxidation can contribute to energy production in the heart, nor whether increasing ketone oxidation increases cardiac efficiency. Therefore, our goal was to determine to what extent high levels of the ketone body, β-hydroxybutyrate (βOHB), contributes to cardiac energy production, and whether this influences cardiac efficiency.

Methods And Results: Isolated working mice hearts were aerobically perfused with palmitate (0.8mM or 1.2mM), glucose (5mM) and increasing concentrations of βOHB (0, 0.6, 2.0mM). Subsequently, oxidation of these substrates, cardiac function and cardiac efficiency were assessed. Increasing βOHB concentrations increased myocardial ketone oxidation rates without affecting glucose or fatty acid oxidation rates where normal physiological levels of glucose (5mM) and fatty acid (0.8mM) are present. Notably, ketones became the major fuel source for the heart at 2.0mM βOHB (at both low or high fatty acid concentrations), with the elevated ketone oxidation rates markedly increasing TCA cycle activity, producing a large amount of reducing equivalents and finally, increasing myocardial oxygen consumption. However, the marked increase in ketone oxidation at high concentrations of βOHB was not accompanied by an increase in cardiac work, suggesting that a mismatch between excess reduced equivalents production from ketone oxidation and cardiac ATP production. Consequently, cardiac efficiency decreased when the heart was exposed to higher ketone levels.

Conclusions: We demonstrate that while ketones can become the major fuel source for the heart, they do not increase cardiac efficiency, which also underscores the importance of recognizing ketones as a major fuel source for the heart in times of starvation, consumption of a ketogenic diet or poorly controlled diabetes.

Translational Perspective: Recent clinical interest has focused on ketones as a potential fuel source for the failing heart, primarily because ketones have been popularized as a "thrifty" fuel that may increase cardiac efficiency. However, we have directly assessed cardiac ketone oxidation rates alongside their competing energy substrates and found that: not only can ketones become the major fuel of the heart with no inhibitory effect on cardiac glucose oxidation, but they can provide the healthy heart with an excess energy supply, with no changes to cardiac function, resulting in a mismatch between reducing equivalents supply and cardiac ATP production, ultimately contributing to a decrease in cardiac efficiency.
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http://dx.doi.org/10.1093/cvr/cvaa143DOI Listing
May 2020

Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation.

Cell Metab 2020 May 9;31(5):909-919.e8. Epub 2020 Apr 9.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada. Electronic address:

Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.
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http://dx.doi.org/10.1016/j.cmet.2020.03.017DOI Listing
May 2020

Cardiovascular biology of the GIP receptor.

Peptides 2020 03 5;125:170228. Epub 2019 Dec 5.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada. Electronic address:

Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted primarily from enteroendocrine K cells in the duodenum and proximal jejunum following nutrient ingestion, primarily acting on islet β-cells to potentiate insulin secretion in a glucose-dependent manner. New discoveries of GIP receptor (GIPR) biology in adipose tissue, as well as findings that co-agonists for the glucagon-like peptide-1 receptor (GLP-1R) and GIPR induce greater weight loss than that seen with GLP-1R agonists alone, has led to continued interest in manipulating GIPR activity for the treatment of obesity/type 2 diabetes mellitus (T2DM). As cardiovascular diseases represent the number one cause of death in people with T2DM, there has also been growing interest in understanding the cardiovascular actions of the GIP/GIPR axis. Although controversy surrounds whether GIPR agonism or antagonism will induce weight loss in obesity/T2DM, such actions undoubtedly will impact cardiovascular function and outcomes since obesity is a major risk factor for cardiovascular disease. Furthermore, GIPR agonism is associated with reduced progression of atherosclerotic lesions in preclinical studies. Conversely, genetic deletion of GIPR activity within cardiac myocytes of the heart results in robust protection against experimental myocardial infarction. Nonetheless, interrogation of the GIP/GIPR axis on cardiac function in humans will involve the systemic actions of the GIPR within the myocardium and other systems (e.g. adipose tissue, vasculature), which will influence the long-term future of GIPR modification for the treatment of obesity/T2DM.
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http://dx.doi.org/10.1016/j.peptides.2019.170228DOI Listing
March 2020

l-Citrulline supplementation improves glucose and exercise tolerance in obese male mice.

Exp Physiol 2020 02 15;105(2):270-281. Epub 2020 Jan 15.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.

New Findings: What is the central question of the study? Does the action of l-citrulline, which has been shown to augment performance in animals and athletes, possibly via increasing mitochondrial function, translate to obese animals, and does this improve glycaemia? What is the main finding and its importance? Chronic supplementation with l-citrulline improves not only exercise capacity, but also glycaemia in obese mice, which would be beneficial as obese individuals are at increased risk for type 2 diabetes. However, l-citrulline supplementation also caused a mild impairment in insulin signalling and insulin tolerance in obese mice. ABSTRACT: l-Citrulline is an organic α-amino acid that has been shown to have a number of salutary actions on whole-body physiology, including reducing muscle wasting and augmenting exercise and muscle performance. The latter has been suggested to arise from elevations in mitochondrial function. Because enhancing mitochondrial function has been proposed as a novel strategy to mitigate insulin resistance, our goal was to determine whether supplementation with l-citrulline could also improve glycaemia in an experimental mouse model of obesity. We hypothesized that l-citrulline treatment would improve glycaemia in obese mice, and this would be associated with elevations in skeletal muscle mitochondrial function. Ten-week-old C57BL/6J mice were fed either a low-fat (10% kcal from lard) or a high-fat (60% kcal from lard) diet, while receiving drinking water supplemented with either vehicle or l-citrulline (0.6 g l ) for 15 weeks. Glucose homeostasis was assessed via glucose/insulin tolerance testing, while in vivo metabolism was assessed via indirect calorimetry, and forced exercise treadmill testing was utilized to assess endurance. As expected, obese mice supplemented with l-citrulline exhibited an increase in exercise capacity, which was associated with an improvement in glucose tolerance. Consistent with augmented mitochondrial function, we observed an increase in whole body oxygen consumption rates in obese mice supplemented with l-citrulline. Surprisingly, l-citrulline supplementation worsened insulin tolerance and reduced insulin signalling in obese mice. Taken together, although l-citrulline supplementation improves both glucose tolerance and exercise capacity in obese mice, caution must be applied with its broad use as a nutraceutical due to a potential deterioration of insulin sensitivity.
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http://dx.doi.org/10.1113/EP088109DOI Listing
February 2020

Dietary-Induced Obesity, Hepatic Cytochrome P450, and Lidocaine Metabolism: Comparative Effects of High-Fat Diets in Mice and Rats and Reversibility of Effects With Normalization of Diet.

J Pharm Sci 2020 02 13;109(2):1199-1210. Epub 2019 Nov 13.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

The effects of a high-fat diet on mRNA and protein of cytochrome P450 (CYP) enzymes in rats and mice and its impact on lidocaine deethylation to its main active metabolite, monoethylglycinexylidide (MEGX), in rats were investigated. The effect of a change in diet from high-fat to standard diet was also evaluated. Plasma biochemistry, mRNA, protein expression for selected CYP, and the activity of lidocaine deethylation were determined. The high-fat diet curtailed the activity and the expression of the majority of CYPs (CYP1A2, CYP3A1, CYP2C11, CYP2C12, and CYP2D1), mRNA levels (Cyp1a2 and Cyp3a2), and MEGX maximal formation rate (Vmax). Mice showed complementary results in their protein expressions of cyp3a and 1a2. Switching the diet back to standard chow in rats for 4 weeks reverted the expression levels of mRNA and protein back to normal levels as well as the maximum formation rates of MEGX. Female and male rodents showed similar patterns in CYP expression and lidocaine metabolism in response to the diets, although MEGX formation was faster in male rats. In conclusion, diet-induced obesity caused general decreases in CYP isoforms not only in rats but also in mice. The effects were shown to be reversible in rats by normalizing the diet.
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http://dx.doi.org/10.1016/j.xphs.2019.11.007DOI Listing
February 2020

A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding interactions.

Bioorg Chem 2019 12 12;93:103269. Epub 2019 Sep 12.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada. Electronic address:

The Forkhead boX M1 (FOXM1) protein is an essential transcription factor required for the normal activation of human cell cycle. However, increasing evidence supports a correlation between FOXM1 overexpression and the onset of several types of cancer. Based on a previously reported molecular modeling and molecular dynamics simulations (MD) study, we hypothesized the role of an essential halogen-bonding interaction between the 4-fluorophenyl group in the forkhead domain inhibitor-6 (FDI-6) and an Arg297 residue inside the FOXM1-DNA binding domain (DBD). To prove the importance of this binding interaction, we synthesized and screened ten FDI-6 derivatives possessing different groups at the 4-fluorophenyl position of the lead molecule. Briefly, we found that derivatives possessing a 4-chlorophenyl, 4-bromophenyl, or a 4-iodophenyl group, were equipotent to the original 4-fluorophenyl moiety present in FDI-6, whereas derivatives without this 4-halogen moiety were inactive. We also observed that positional isomers in which the halogen was relocated to positions 2- or 3- on the phenyl group were significantly less active. These results provide evidence to support the essential role of a 4-halophenyl bonding interaction, with the Arg297 residue in the FOXM1-DBD, to exert inhibition of transcriptional activity.
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http://dx.doi.org/10.1016/j.bioorg.2019.103269DOI Listing
December 2019

Malonyl CoA Decarboxylase Inhibition Improves Cardiac Function Post-Myocardial Infarction.

JACC Basic Transl Sci 2019 Jun 24;4(3):385-400. Epub 2019 Jun 24.

Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

Alterations in cardiac energy metabolism after a myocardial infarction contribute to the severity of heart failure (HF). Although fatty acid oxidation can be impaired in HF, it is unclear if stimulating fatty acid oxidation is a desirable approach to treat HF. Both immediate and chronic malonyl coenzyme A decarboxylase inhibition, which decreases fatty acid oxidation, improved cardiac function through enhancing cardiac efficiency in a post-myocardial infarction rat that underwent permanent left anterior descending coronary artery ligation. The beneficial effects of MCD inhibition were attributed to a decrease in proton production due to an improved coupling between glycolysis and glucose oxidation.
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http://dx.doi.org/10.1016/j.jacbts.2019.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609914PMC
June 2019

Role of Cytochrome p450 and Soluble Epoxide Hydrolase Enzymes and Their Associated Metabolites in the Pathogenesis of Diabetic Cardiomyopathy.

J Cardiovasc Pharmacol 2019 09;74(3):235-245

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.

A plethora of studies have demonstrated that cardiomyopathy represents a serious source of morbidity and mortality in patients with diabetes. Yet, the underlying mechanisms of diabetic cardiomyopathy are still poorly understood. Of interest, cytochrome P450 2J (CYP2J) and soluble epoxide hydrolase (sEH) are known to control the maintenance of cardiovascular health through the regulation of cardioprotective epoxyeicosatrienoic acids (EETs) and its less active products, dihydroxyeicosatrienoic acids (DHETs). Therefore, we examined the role of the aforementioned pathway in the development of diabetic cardiomyopathy. Our diabetic model initiated cardiomyopathy as indexed by the increase in the expression of hypertrophic markers such as NPPA. Furthermore, diabetic cardiomyopathy was associated with a low level of cardiac EETs and an increase of the DHETs/EETs ratio both in vivo and in cardiac cells. The modulation in EETs and DHETs was attributed to the increase of sEH and the decrease of CYP2J. Interestingly, the reduction of sEH attenuates cardiotoxicity mediated by high glucose in cardiac cells. Mechanistically, the beneficial effect of sEH reduction might be due to the decrease of phosphorylated ERK1/2 and p38. Overall, the present work provides evidence that diabetes initiates cardiomyopathy through the increase in sEH, the reduction of CYP2J, and the decrease of cardioprotective EETs.
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http://dx.doi.org/10.1097/FJC.0000000000000707DOI Listing
September 2019

Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure.

Cardiovasc Diabetol 2019 07 5;18(1):86. Epub 2019 Jul 5.

Cardiovascular Research Centre, University of Alberta, 423 Heritage Medical Research Centre, Edmonton, T6G 2S2, Canada.

Background: Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure.

Method: For human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day).

Result: Echocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups.

Conclusion: We conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.
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http://dx.doi.org/10.1186/s12933-019-0892-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610921PMC
July 2019

Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency.

Cardiovasc Res 2019 09;115(11):1606-1616

Cardiovascular Research Centre, Faculty of Medicine and Dentistry, 423 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, Canada.

Aims: The failing heart is energy-starved and inefficient due to perturbations in energy metabolism. Although ketone oxidation has been shown recently to increase in the failing heart, it remains unknown whether this improves cardiac energy production or efficiency. We therefore assessed cardiac metabolism in failing hearts and determined whether increasing ketone oxidation improves cardiac energy production and efficiency.

Methods And Results: C57BL/6J mice underwent sham or transverse aortic constriction (TAC) surgery to induce pressure overload hypertrophy over 4-weeks. Isolated working hearts from these mice were perfused with radiolabelled β-hydroxybutyrate (βOHB), glucose, or palmitate to assess cardiac metabolism. Ejection fraction decreased by 45% in TAC mice. Failing hearts had decreased glucose oxidation while palmitate oxidation remained unchanged, resulting in a 35% decrease in energy production. Increasing βOHB levels from 0.2 to 0.6 mM increased ketone oxidation rates from 251 ± 24 to 834 ± 116 nmol·g dry wt-1 · min-1 in TAC hearts, rates which were significantly increased compared to sham hearts and occurred without decreasing glycolysis, glucose, or palmitate oxidation rates. Therefore, the contribution of ketones to energy production in TAC hearts increased to 18% and total energy production increased by 23%. Interestingly, glucose oxidation, in parallel with total ATP production, was also significantly upregulated in hearts upon increasing βOHB levels. However, while overall energy production increased, cardiac efficiency was not improved.

Conclusions: Increasing ketone oxidation rates in failing hearts increases overall energy production without compromising glucose or fatty acid metabolism, albeit without increasing cardiac efficiency.
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http://dx.doi.org/10.1093/cvr/cvz045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704391PMC
September 2019

Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity.

Sci Transl Med 2019 02;11(478)

Department of Medicine, University of Alberta, Edmonton, Alberta T6G 2J7, Canada.

Chemotherapy-induced cardiotoxicity (CIC) is a common clinical problem that compromises effective anticancer therapies. Many chemotherapeutics (including anthracyclines, such as doxorubicin) induce the proapoptotic transcription factor p53 in the tumor and nonspecifically in the heart, promoting heart failure. Although inhibition of p53 shows benefit in preclinical heart failure models, it would not be an attractive adjuvant therapy for CIC, because it would prevent tumor regression. A p53-targeting therapy that would decrease chemotherapy-induced apoptosis in the myocardium and, at the same time, enhance apoptosis in the tumor would be ideal. Here, we propose that differences in oxygen tension between the myocardium and the tumor could provide a platform for redox-dependent tissue-specific therapies. We show by coimmunoprecipitation and mass spectrometry that the redox-regulated pyruvate kinase muscle 2 (PKM2) directly binds with p53 and that the redox status of cysteine-423 of tetrameric (but not monomeric) PKM2 is critical for the differential regulation of p53 transcriptional activity. Tetrameric PKM2 suppresses p53 transcriptional activity and apoptosis in a high oxidation state but enhances them in a low oxidation one. We show that the oxidation state (along with cysteine-423 oxidation) is higher in the heart compared to the tumor of the same animal. Treatment with TEPP-46 (a compound that stabilizes tetrameric PKM2) suppressed doxorubicin-induced cardiomyocyte apoptosis, preventing cardiac dysfunction, but enhanced cancer cell apoptosis and tumor regression in the same animals in lung cancer models. Thus, our work suggests that redox-dependent differences in common proteins expressed in the myocardium and tumor can be exploited therapeutically for tissue selectivity in CIC.
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http://dx.doi.org/10.1126/scitranslmed.aau8866DOI Listing
February 2019

The antianginal ranolazine mitigates obesity-induced nonalcoholic fatty liver disease and increases hepatic pyruvate dehydrogenase activity.

JCI Insight 2019 01 10;4(1). Epub 2019 Jan 10.

Faculty of Pharmacy and Pharmaceutical Sciences.

Obese individuals are often at risk for nonalcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes (T2D), and cardiovascular diseases such as angina, thereby requiring combination therapies for their comorbidities. Ranolazine is a second-line antianginal agent that also improves glycemia, and our aim was to determine whether ranolazine modifies the progression of obesity-induced NAFLD. Twelve-week-old C57BL/6J male mice were fed a low-fat or high-fat diet for 10 weeks and then treated for 30 days with either vehicle control or ranolazine (50 mg/kg via daily s.c. injection). Glycemia was monitored via glucose/pyruvate/insulin tolerance testing, whereas in vivo metabolism was assessed via indirect calorimetry. Hepatic triacylglycerol content was quantified via the Bligh and Dyer method. Consistent with previous reports, ranolazine treatment reversed obesity-induced glucose intolerance, which was associated with reduced body weight and hepatic steatosis, as well as increased hepatic pyruvate dehydrogenase (PDH) activity. Ranolazine's actions on hepatic PDH activity may be directly mediated, as ranolazine treatment reduced PDH phosphorylation (indicative of increased PDH activity) in HepG2 cells. Therefore, in addition to mitigating angina, ranolazine also reverses NAFLD, which may contribute to its documented glucose-lowering actions, situating ranolazine as an ideal antianginal therapy for obese patients comorbid for NAFLD and T2D.
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http://dx.doi.org/10.1172/jci.insight.124643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485361PMC
January 2019

Targeting the glucagon receptor improves cardiac function and enhances insulin sensitivity following a myocardial infarction.

Cardiovasc Diabetol 2019 01 9;18(1). Epub 2019 Jan 9.

Cardiovascular Research Centre, 423 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada.

Background: In heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon's action on cardiac glucose and lipid homeostasis counteract that of insulin's action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI).

Methods: Male C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4 mg kg week starting at 1 week post-MI) for 3 weeks.

Results: Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0 ± 2.3% vs 30.7 ± 1.7% in vehicle-treated MI heart, p < 0.05) and limited adverse remodelling (LV mass: 129 ± 7 vs 176 ± 14 mg in vehicle-treated MI hearts, p < 0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661 ± 192 vs 924 ± 165 nmol g dry wt min in vehicle-treated MI hearts, p < 0.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3β pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374 ± 27 vs 183 ± 41 µmol g protein in vehicle-treated MI hearts, p < 0.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor β-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment.

Conclusions: mAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.
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http://dx.doi.org/10.1186/s12933-019-0806-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325856PMC
January 2019

Glucagon-like peptide-1 receptor action in the vasculature.

Peptides 2019 01 15;111:26-32. Epub 2018 Sep 15.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, Canada. Electronic address:

Glucagon-like peptide-1 receptor (GLP-1R) agonists augment insulin secretion and are thus used clinically to improve glycemia in subjects with type 2 diabetes (T2D). As recent data reveal marked improvements in cardiovascular outcomes in T2D subjects treated with the GLP-1R agonists liraglutide and semaglutide in the LEADER and SUSTAIN-6 clinical trials respectively, there is growing interest in delineating the mechanism(s) of action for GLP-1R agonist-induced cardioprotection. Of importance, negligible GLP-1R expression in ventricular cardiac myocytes suggests that cardiac-independent actions of GLP-1R agonists may account for the reduced death rates from cardiovascular causes in T2D subjects enrolled in the LEADER trial. Conversely, vascular smooth muscle cells (VSMCs) appear to express the canonical GLP-1R, and GLP-1/GLP-1R agonists exhibit a number of salutary actions on the vascular endothelium that could potentially contribute to GLP-1R agonists directly improving cardiovascular outcomes in subjects with T2D. We review herein the described actions of GLP-1/GLP-1R agonists on the vascular endothelium, which include antiproliferative actions on VSMCs and endothelial cells, reductions in oxidative stress, and increases in nitric oxide generation. GLP-1 also increases microvascular recruitment and microvascular blood flow. Taken together, such actions may explain the antihypertensive and/or antiatherosclerotic actions attributed to GLP-1/GLP-1R agonists in preclinical and clinical studies. Nonetheless, further mechanistic studies are still necessary to determine the relative importance of such actions in accounting for reductions in macrovascular cardiovascular disease in human subjects with T2D treated with GLP-1R agonists.
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http://dx.doi.org/10.1016/j.peptides.2018.09.002DOI Listing
January 2019

Skeletal muscle-specific Cre recombinase expression, controlled by the human α-skeletal actin promoter, improves glucose tolerance in mice fed a high-fat diet.

Diabetologia 2018 08 1;61(8):1849-1855. Epub 2018 Jun 1.

Katz Centre for Pharmacy and Health Research, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, T6G 2E1, Canada.

Aims/hypothesis: Cre-loxP systems are frequently used in mouse genetics as research tools for studying tissue-specific functions of numerous genes/proteins. However, the expression of Cre recombinase in a tissue-specific manner often produces undesirable changes in mouse biology that can confound data interpretation when using these tools to generate tissue-specific gene knockout mice. Our objective was to characterise the actions of Cre recombinase in skeletal muscle, and we anticipated that skeletal muscle-specific Cre recombinase expression driven by the human α-skeletal actin (HSA) promoter would influence glucose homeostasis.

Methods: Eight-week-old HSA-Cre expressing mice and their wild-type littermates were fed a low- or high-fat diet for 12 weeks. Glucose homeostasis (glucose/insulin tolerance testing) and whole-body energy metabolism (indirect calorimetry) were assessed. We also measured circulating insulin levels and the muscle expression of key regulators of energy metabolism.

Results: Whereas tamoxifen-treated HSA-Cre mice fed a low-fat diet exhibited no alterations in glucose homeostasis, we observed marked improvements in glucose tolerance in tamoxifen-treated, but not corn-oil-treated, HSA-Cre mice fed a high-fat diet vs their wild-type littermates. Moreover, Cre dissociation from heat shock protein 90 and translocation to the nucleus was only seen following tamoxifen treatment. These improvements in glucose tolerance were not due to improvements in insulin sensitivity/signalling or enhanced energy metabolism, but appeared to stem from increases in circulating insulin.

Conclusions/interpretation: The intrinsic glycaemia phenotype in the HSA-Cre mouse necessitates the use of HSA-Cre controls, treated with tamoxifen, when using Cre-loxP models to investigate skeletal muscle-specific gene/protein function and glucose homeostasis.
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http://dx.doi.org/10.1007/s00125-018-4643-xDOI Listing
August 2018

Glucagon-like peptide-1 receptor mediated control of cardiac energy metabolism.

Peptides 2018 02;100:94-100

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB Canada; Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB Canada. Electronic address:

Glucagon-like peptide-1 receptor (GLP-1R) agonists are frequently used to improve glycemia in patients with type 2 diabetes (T2D). Recent data from cardiovascular outcomes trials for the GLP-1R agonists, liraglutide and semaglutide, have also demonstrated significant reductions in death rates from cardiovascular causes in patients with T2D. As cardiovascular death is the number one cause of death in patients with T2D, understanding the mechanisms by which GLP-1R agonists such as liraglutide and semaglutide improve cardiac function is essential. Yet despite strong evidence from preclinical and clinical studies supporting the cardioprotective actions of GLP-1R agonists, the precise mechanism(s) by which this drug-class for T2D may produce these beneficial actions remains enigmatic. Negligible GLP-1R expression in ventricular cardiac myocytes suggests that GLP-1R agonist-induced cardioprotection is likely partially attributed to indirect actions on peripheral tissues other than the heart. Because insulin increases glucose oxidation, whereas glucagon increases fatty acid oxidation in the heart, GLP-1R agonist-induced increases and decreases in insulin and glucagon secretion, respectively, may modify cardiac energy metabolism in T2D patients. This may represent a potential mechanism for GLP-1R agonist-induced cardioprotection in T2D, as increases in fatty acid oxidation and decreases in glucose oxidation are frequently observed in the hearts of animals and human subjects with T2D.
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http://dx.doi.org/10.1016/j.peptides.2017.12.005DOI Listing
February 2018

Inactivation of the Glucose-Dependent Insulinotropic Polypeptide Receptor Improves Outcomes following Experimental Myocardial Infarction.

Cell Metab 2018 02 21;27(2):450-460.e6. Epub 2017 Dec 21.

Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada. Electronic address:

Incretin hormones exert pleiotropic metabolic actions beyond the pancreas. Although the heart expresses both incretin receptors, the cardiac biology of GIP receptor (GIPR) action remains incompletely understood. Here we show that GIPR agonism did not impair the response to cardiac ischemia. In contrast, genetic elimination of the Gipr reduced myocardial infarction (MI)-induced ventricular injury and enhanced survival associated with reduced hormone sensitive lipase (HSL) phosphorylation; it also increased myocardial triacylglycerol (TAG) stores. Conversely, direct GIPR agonism in the isolated heart reduced myocardial TAG stores and increased fatty acid oxidation. The cardioprotective phenotype in Gipr mice was partially reversed by pharmacological activation or genetic overexpression of HSL. Selective Gipr inactivation in cardiomyocytes phenocopied Gipr mice, resulting in improved survival and reduced adverse remodeling following experimental MI. Hence, the cardiomyocyte GIPR regulates fatty acid metabolism and the adaptive response to ischemic cardiac injury. These findings have translational relevance for developing GIPR-based therapeutics.
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http://dx.doi.org/10.1016/j.cmet.2017.11.003DOI Listing
February 2018

Decreased Maternal Cardiac Glucose Oxidation: Taking One for the Fetus.

Circ Res 2017 12;121(12):1299-1301

From the Department of Pediatrics, University of Alberta (G.D.L.), Faculty of Pharmacy and Pharmaceutical Sciences (J.R.U.), and Women and Children's Health Research Institute (J.R.U., G.D.L.), University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.1161/CIRCRESAHA.117.312098DOI Listing
December 2017

The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice.

Mol Metab 2017 11 1;6(11):1339-1349. Epub 2017 Sep 1.

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Canada. Electronic address:

Objectives: Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice.

Methods: The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1r). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo.

Results: Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1r mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1r mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart.

Conclusions: GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.
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http://dx.doi.org/10.1016/j.molmet.2017.08.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681270PMC
November 2017

Female offspring born to obese and insulin-resistant dams are not at increased risk for obesity and metabolic dysfunction during early development.

Can J Physiol Pharmacol 2018 Jan 8;96(1):97-102. Epub 2017 Sep 8.

a Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, Canada.

The percentage of women who are obese at the time of conception or during pregnancy is increasing, with animal and human studies demonstrating that offspring born to obese dams or mothers are at increased risk for obesity and the metabolic syndrome. Our goal was to confirm in an experimental model of metabolic syndrome in the dam, whether the offspring would be at increased risk of obesity. Conversely, we observed that male offspring born to dams with metabolic syndrome had no alterations in their body mass profiles, whereas female offspring born to dams with metabolic syndrome were heavier at weaning, but exhibited no perturbations in energy metabolism. Moreover, they gained weight at a reduced rate versus female offspring born to healthy dams, and thus weighed less at study completion. Hence, our findings suggest that factors other than increased adiposity and insulin resistance during pregnancy are responsible for the increased risk of obesity in children born to obese mothers.
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http://dx.doi.org/10.1139/cjpp-2017-0371DOI Listing
January 2018

FoxO1 regulates myocardial glucose oxidation rates via transcriptional control of pyruvate dehydrogenase kinase 4 expression.

Am J Physiol Heart Circ Physiol 2017 Sep 7;313(3):H479-H490. Epub 2017 Jul 7.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada;

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation and a critical regulator of metabolic flexibility during the fasting to feeding transition. PDH is regulated via both PDH kinases (PDHK) and PDH phosphatases, which phosphorylate/inactivate and dephosphorylate/activate PDH, respectively. Our goal was to determine whether the transcription factor forkhead box O1 (FoxO1) regulates PDH activity and glucose oxidation in the heart via increasing the expression of , the gene encoding PDHK4. To address this question, we differentiated H9c2 myoblasts into cardiac myocytes and modulated FoxO1 activity, after which /PDHK4 expression and PDH phosphorylation/activity were assessed. We assessed binding of FoxO1 to the promoter in cardiac myocytes in conjunction with measuring the role of FoxO1 on glucose oxidation in the isolated working heart. Both pharmacological (1 µM AS1842856) and genetic (siRNA mediated) inhibition of FoxO1 decreased /PDHK4 expression and subsequent PDH phosphorylation in H9c2 cardiac myocytes, whereas 10 µM dexamethasone-induced /PDHK4 expression was abolished via pretreatment with 1 µM AS1842856. Furthermore, transfection of H9c2 cardiac myocytes with a vector expressing FoxO1 increased luciferase activity driven by a promoter construct containing the FoxO1 DNA-binding element region, but not in a promoter construct lacking this region. Finally, AS1842856 treatment in fasted mice enhanced glucose oxidation rates during aerobic isolated working heart perfusions. Taken together, FoxO1 directly regulates transcription in the heart, thereby controlling PDH activity and subsequent glucose oxidation rates. Although studies have shown an association between FoxO1 activity and pyruvate dehydrogenase kinase 4 expression, our study demonstrated that pyruvate dehydrogenase kinase 4 is a direct transcriptional target of FoxO1 (but not FoxO3/FoxO4) in the heart. Furthermore, we report here, for the first time, that FoxO1 inhibition increases glucose oxidation in the isolated working mouse heart.
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http://dx.doi.org/10.1152/ajpheart.00191.2017DOI Listing
September 2017

Revisiting protein acetylation and myocardial fatty acid oxidation.

Am J Physiol Heart Circ Physiol 2017 09 23;313(3):H617-H619. Epub 2017 Jun 23.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada;

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http://dx.doi.org/10.1152/ajpheart.00303.2017DOI Listing
September 2017

Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway.

Mol Metab 2017 06 31;6(6):503-511. Epub 2017 Mar 31.

The Department of Medicine, University of Toronto, Canada.

Objective: Glucagon-like peptides (GLPs) are secreted from enteroendocrine cells in response to nutrients and bile acids and control metabolism via actions on structurally-related yet distinct G protein coupled receptors. GLP-1 regulates gut motility, appetite, islet function, and glucose homeostasis, whereas GLP-2 enhances intestinal nutrient absorption. GLP-1R agonists are used to treat diabetes and obesity, and a GLP-2R agonist is approved to treat short bowel syndrome. Unexpectedly, reports of gallbladder disease have been associated with the use of both GLP-1R and GLP-2R agonists and after bariatric surgery, although the mechanisms remain unknown.

Methods: We investigated whether GLP-1 or GLP-2 acutely controls gallbladder (GB) volume and whether GLP-2 regulates GB muscle activity in mice. The expression of , , and was assessed in mouse GB, and the effects of GLP-2 on hepatic bile acid (BA) flow, intestinal and liver BA uptake, and GB gene expression were determined. GLP-2 regulation of GB volume was assessed in wildtype, and mice. The effect of GLP-2 on GB smooth muscle (GBSM) calcium transients was characterized .

Results: Acute administration of the GLP-1R agonist exendin-4 lowered glucose but had no effect on GB volume in mice. In contrast, GLP-2 rapidly enhanced GB filling in a dose-dependent manner, actions maintained in the presence of cholecystokinin, and mediated through the canonical GLP-2R. GLP-2 also rapidly induced immediate early gene expression in GB, consistent with detection of the endogenous in GB RNA. The ability of GLP-2 to increase GB volume was not abrogated by systemic administration of hexamethonium, propranolol, a vasoactive peptide receptor antagonist or N-Nitroarginine methyl ester, and was maintained in mice. In contrast, lithocholic acid, a Tgr5 agonist, increased GB filling in but not in mice. GLP-2 had no effect on ileal uptake or hepatic clearance of taurocholic acid or on hepatic bile flow, yet reduced the frequency of spontaneous calcium transients in murine GBSM , in a tetrodotoxin-sensitive manner.

Conclusions: Our data extend endocrine concepts of regulation of GB filling beyond FXR-FGF15/19 and the direct effects of BA via Tgr5, to encompass a novel BA-Tgr5-L cell GLP-2 axis providing nutrient-mediated feedback from BA to terminate meal-related GB contraction. These findings have implications for conditions characterized by elevated circulating levels of GLP-2 such as after bariatric surgery and the development and use of agents that promote Tgr5 activation, L cell secretion, or GLP-2R agonism for the treatment of metabolic disease.
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http://dx.doi.org/10.1016/j.molmet.2017.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444019PMC
June 2017

Evolving Concepts of Myocardial Energy Metabolism: More Than Just Fats and Carbohydrates.

Circ Res 2016 11;119(11):1173-1176

From the Cardiovascular Translational Science Institute (G.D.L., J.R.U.), Alberta Diabetes Institute (G.D.L., J.R.U.), Faculty of Pharmacy and Pharmaceutical Sciences (J.R.U.), and Department of Pediatrics (G.D.L.), University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.1161/CIRCRESAHA.116.310078DOI Listing
November 2016