Fatty acid metabolism is enhanced in type 2 diabetic hearts

Carley, Andrew N.; Severson, David L.

doi:10.1016/j.bbalip.2005.03.005

Cited by 232Cardiovascular Function and Risk FactorsLipid metabolism and biosynthesisPeroxisome Proliferator-Activated Receptors

Fatty acid metabolism is enhanced in type 2 diabetic hearts

Carley, Andrew N., Severson, David L.·2005·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

DOI 10.1016/j.bbalip.2005.03.005

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Abstract

The metabolic phenotype of hearts has been investigated using rodent models of type 2 diabetes which exhibit obesity and insulin resistance: db/db and ob/ob mice, and Zucker fatty and ZDF rats. In general, cardiac fatty acid (FA) utilization is enhanced in type 2 diabetic hearts, with increased rates of FA oxidation (db/db, ob/ob and ZDF models) and increased FA esterification into cellular triacylglycerols (db/db hearts). Hearts from db/db and ob/ob mice and ZDF rat hearts all have elevated levels of myocardial triacylglycerols, consistent with enhanced FA utilization. A number of mechanisms may be responsible for enhanced FA utilization in type 2 diabetic hearts: (i) increased FA uptake into cardiac myocytes and into mitochondria; (ii) altered mitochondrial function, with up-regulation of uncoupling proteins; and (iii) stimulation of peroxisome proliferator-activated receptor-alpha. Enhanced cardiac FA utilization in rodent type 2 diabetic models is associated with reduced cardiac contractile function, perhaps as a consequence of lipotoxicity and/or reduced cardiac efficiency. Similar results have been obtained with human type 2 diabetic hearts, suggesting that pharmacological interventions that can reduce cardiac FA utilization may have beneficial effects on contractile function.

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Diabetes impairs glucose uptake and results in an increase in fatty acid metabolism in cardiac tissue.
“Diabetes impairs glucose uptake and results in an increase in fatty acid (FA) metabolism in cardiac tissue [3, 8, 9].”
From Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population (2016) · cites this paper as [9]
In diabetes, decreased insulin signaling activates transcriptional signaling pathways that induce the expression of genes involved in stimulating FA uptake; however, the uptake of FAs exceeds metabolic demand and results in triglyceride and cholesterol accumulation in the myocardium which impairs diastolic function.
“In diabetes, decreased insulin signaling activates transcriptional signaling pathways that induce the expression of genes involved in stimulating FA uptake; however the uptake of FAs exceeds metabolic demand and results in triglyceride and cholesterol accumulation in the myocardium which impairs diastolic function [8-11].”
From Role of Serum Biomarkers in Early Detection of Diabetic Cardiomyopathy in the West Virginian Population (2016) · cites this paper as [9]
Diabetes is associated with shifts in myocardial substrate utilization characterized by an increase in FA utilization and a decrease in glucose utilization.
“It has long been known that diabetes is associated with shifts in myocardial substrate utilization characterized by an increase in FA utilization and a decrease in glucose utilization (37, 315).”
From Cardiac remodeling in obesity (2008) · cites this paper as [37]

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Palmitate-mediated Alterations in the Fatty Acid Metabolism of Rat Neonatal Cardiac Myocytes
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Peroxisome Proliferator-activated Receptor α (PPARα) Signaling in the Gene Regulatory Control of Energy Metabolism in the Normal and Diseased Heart
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Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-α activator
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Self-citation
Sulfo-N-succinimidyl esters of long chain fatty acids specifically inhibit fatty acid translocase (FAT/CD36)-mediated cellular fatty acid uptake
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Overexpression of Apolipoprotein B in the Heart Impedes Cardiac Triglyceride Accumulation and Development of Cardiac Dysfunction in Diabetic Mice
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Insulin inhibition of 5′ adenosine monophosphate—activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation
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Routes of FA delivery to cardiac muscle: modulation of lipoprotein lipolysis alters uptake of TG-derived FA
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Mechanism for obesity-induced increase in myocardial lipid peroxidation
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Genes for Apolipoprotein B and Microsomal Triglyceride Transfer Protein Are Expressed in the Heart
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Self-citation
Apo B100-containing lipoproteins are secreted by the heart.
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New insights into long-chain fatty acid uptake by heart muscle: a crucial role for fatty acid translocase/CD36
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Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats
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Patients with early diabetic heart disease demonstrate a normal myocardial response to dobutamine
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Differences in the sensitivity of carnitine palmitoyltransferase to inhibition by malonyl-CoA are due to differences in Ki values.
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Diabetic cardiomyopathy: recent evidence from mouse models of type 1 and type 2 diabetes
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Self-citation
Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm
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Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids
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Role of FATP in parenchymal cell fatty acid uptake
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PPAR-α effects on the heart and other vascular tissues
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Contribution of malonyl-CoA decarboxylase to the high fatty acid oxidation rates seen in the diabetic heart
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Influence of metabolic substrate on rat heart function and metabolism at different coronary flows
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Malonyl CoA Control of Fatty Acid Oxidation in the Ischemic Heart
Dyck, J. R. B., & Lopaschuk, G. D. (2002) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2002.2060 · Cited by 99 · see citing works
Mouse models of mitochondrial dysfunction and heart failure
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Evidence for mitochondrial thioesterase 1 as a peroxisome proliferator-activated receptor-α-regulated gene in cardiac and skeletal muscle
Stavinoha, M. A., RaySpellicy, J. W., Essop, M. F., Graveleau, C., Abel, E. D., Hart-Sailors, M. L., Mersmann, H. J., Bray, M. S., & Young, M. E. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00190.2004 · Cited by 95 · see citing works
Apolipoprotein B Production Reduces Lipotoxic Cardiomyopathy
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Treatment of type 2 diabeticdb/dbmice with a novel PPARγ agonist improves cardiac metabolism but not contractile function
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Self-citation
Defective Oxidative Metabolism of Heart Mitochondria from Genetically Diabetic Mice
Kuo, T. H., Moore, K. H., Giacomelli, F., & Wiener, J. (1983) · Diabetes · doi:10.2337/diab.32.9.781 · Cited by 93 · see citing works
AMP-activated protein kinase: the guardian of cardiac energy status
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Dichloroacetate improves postischemic function of hypertrophied rat hearts
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Lipoprotein Secretion and Triglyceride Stores in the Heart
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Abnormal mechanical function in diabetes
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Peroxisomal Fatty Acid Oxidation Is a Substantial Source of the Acetyl Moiety of Malonyl-CoA in Rat Heart
Reszko, A. E., Kasumov, T., David, F., Jobbins, K. A., Thomas, K. R., Hoppel, C. L., Brunengraber, H., & Rosiers, C. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400162200 · Cited by 82 · see citing works
Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart
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Differential modulation of glucose, lactate, and pyruvate oxidation by insulin and dichloroacetate in the rat heart
Lloyd, S. G., Brocks, C. A., & Chatham, J. C. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01117.2002 · Cited by 77 · see citing works
Differential Regulation of Carnitine Palmitoyltransferase-I Gene Isoforms (CPT-I and CPT-I ) in the Rat Heart
Cook, G. A., Edwards, T. L., Jansen, M. S., Bahouth, S. W., Wilcox, H. G., & Park, E. A. (2001) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2000.1304 · Cited by 75 · see citing works
Lipoprotein composition as a component in the lipoprotein clearance defect in experimental diabetes.
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Overexpression of UCP-3 in Skeletal Muscle of Mice Results in Increased Expression of Mitochondrial Thioesterase mRNA
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Profiling substrate fluxes in the isolated working mouse heart using 13 C-labeled substrates: focusing on the origin and fate of pyruvate and citrate carbons
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Streptozotocin treatment upregulates uncoupling protein 3 expression in the rat heart.
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Ketone bodies disturb fatty acid handling in isolated cardiomyocytes derived from control and diabetic rats
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Palmitate-induced cardiac apoptosis is mediated through CPT-1 but not influenced by glucose and insulin
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Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI
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Heart failure: how big is the problem? who are the patients? what does the future hold?
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Metabolic effects of insulin on cardiomyocytes from control and diabeticdb/dbmouse hearts
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Self-citation
Utilisation of triacylglycerol and non-esterified fatty acid by the working rat heart: myocardial lipid substrate preference
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Glycation of very low density lipoprotein from rat plasma impairs its catabolism
Mamo, J. C. L., Szeto, L., & Steiner, G. A. (1990) · Diabetologia · doi:10.1007/bf00404637 · Cited by 54 · see citing works
Utilization of triacylglycerol‐rich lipoproteins by the working rat heart: routes of uptake and metabolic fates
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Lipoprotein alterations in 10- and 20-week-old Zucker diabetic fatty rats: Hyperinsulinemic versus insulinopenic hyperglycemia
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The capillary transport system for free fatty acids in the heart.
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Chylomicron and palmitate metabolism by perfused hearts from diabetic mice
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Self-citation
Partial inhibition of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia
Chandler, M. (2003) · Cardiovascular Research · doi:10.1016/s0008-6363(03)00327-4 · Cited by 47 · see citing works
Effects of Trimetazidine on Left Ventricular Function in Patients with Type 2 Diabetes and Heart Failure
Thrainsdottir, I. S., von Bibra, H., Malmberg, K., et al. (2004) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-200407000-00014 · Cited by 46 · see citing works
Left‐ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR‐α or ‐γ agonists in a type 2 diabetic animal model
Kim, S. K., Zhao, Z. S., Lee, Y.-J., Lee, K. E., Kang, S., Choi, D., Lim, S., Chung, N., Lee, H. C., & Soo, B. (2003) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.410 · Cited by 45 · see citing works
Regulation of myocardial triacylglycerol synthesis and metabolism
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High levels of myocardial antioxidant defense in aging nondiabetic normotensive Zucker obese rats
Conti, M., Renaud, I. M., Poirier, B., Michel, O., Belair, M., Mandet, C., Bruneval, P., Myara, I., & Chevalier, J. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00521.2002 · Cited by 39 · see citing works
Diabetes Mellitus and Heart Failure
Jagasia, D., & McNulty, P. H. (2003) · Congestive Heart Failure · doi:10.1111/j.1527-5299.2002.00901.x · Cited by 38 · see citing works
The role of the peroxisome proliferator-activated receptor alpha pathway in pathological remodeling of the diabetic heart
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Differential modulation of citrate synthesis and release by fatty acids in perfused working rat hearts
Vincent, G., Bouchard, B., Khairallah, M., & Rosiers, C. D. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00717.2003 · Cited by 33 · see citing works
Heart-type fatty acid-binding protein reciprocally regulates glucose and fatty acid utilization during exercise
Shearer, J., Fueger, P. T., Rottman, J. N., Bracy, D. P., Binas, B., & Wasserman, D. H. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00287.2004 · Cited by 33 · see citing works
Carnitine palmitoyltransferase in the heart is controlled by a different mechanism than the hepatic enzyme
Cook, G. A., & Lappi, M. D. (1992) · Molecular and Cellular Biochemistry · doi:10.1007/bf01270567 · Cited by 30 · see citing works
Mitochondrial effects with ceramide-induced cardiac apoptosis are different from those of palmitate
Kong, J. Y., & Rabkin, S. W. (2003) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(03)00008-0 · Cited by 28 · see citing works
Myocardial carnitine palmitoyltransferase of the mitochondrial outer membrane is not altered by fasting
Mynatt, R. L., Lappi, M. D., & Cook, G. A. (1992) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(92)90263-u · Cited by 27 · see citing works
Diabetes Mellitus and Heart Failure
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The source of malonyl‐CoA in rat heart
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Concordant mRNA Expression of UCP-3, but Not UCP-2, with Mitochondrial Thioesterase-1 in Brown Adipose Tissue and Skeletal Muscle in db/db Diabetic Mice
Clapham, J. C., Coulthard, V. H., & Moore, G. B. T. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5698 · Cited by 25 · see citing works
Evaluation of Free Fatty Acid Metabolism in Vivo
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UCP3 and its putative function: consistencies and controversies
Harper, M., Dent, R., Bézaire, V., Antoniou, A., Gauthier, A., Monemdjou, S., & McPherson, R. (2001) · Biochemical Society Transactions · doi:10.1042/bst0290768 · Cited by 24 · see citing works
AMPK stimulation increases LCFA but not glucose clearance in cardiac muscle in vivo
Shearer, J., Fueger, P. T., Rottman, J. N., Bracy, D. P., Martin, P. H., & Wasserman, D. H. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00125.2004 · Cited by 21 · see citing works
Chylomicron metabolism by the isolated perfused mouse heart
Mardy, K., Belke, D. D., & Severson, D. L. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.2.e357 · Cited by 19 · see citing works
Self-citation
Pyruyate Dehydrogenase Activity in Cardiac Mitochondria from Genetically Diabetic Mice
Kuo, T. H., Giacomelli, F., Wiener, J., & Lapanowski, K. (1985) · Diabetes · doi:10.2337/diab.34.11.1075 · Cited by 19 · see citing works
Mitochondrial uncoupling proteins as potential targets for pharmacological agents
Harper, M., & Gerrits, M. F. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.06.006 · Cited by 17 · see citing works
Demonstration of reverse fatty acid transport from rat cardiomyocytes
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Mitochondria respiration and susceptibility to ischemia–reperfusion injury in diabetic hearts
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Insulin-treated Zucker diabetic fatty rats retain the hypertriglyceridemia associated with obesity
Sparks, J. D., Shaw, W. N., Corsetti, J. P., et al. (2000) · Metabolism · doi:10.1053/meta.2000.17736 · Cited by 15 · see citing works
A Comparative Study of Responses to Acute Hypoglycaemia Induced by Human and Porcine Insulins in Patients with Type 1 Diabetes
MacLeod, K. M., Gold, A. E., & Frier, B. M. (1996) · Diabetic Medicine · doi:10.1002/(sici)1096-9136(199604)13:4 · Cited by 8 · see citing works
Diabetes and Cardiac Dysfunction
Severson, D. L., Aasum, E., Belke, D. D., Larsen, T. S., Semeniuk, L., & Shimoni, Y. (2003) · Progress in experimental cardiology · doi:10.1007/978-1-4419-9232-1_29 · Cited by 7 · see citing works
Self-citation
UCP3 gene expression does not correlate with muscle oxidation rates in troglitazone-treated Zucker fatty rats
Oberkofler, H., Neschen, S., Esterbauer, H., Waldhäusl, W. K., Patsch, W., & Fürnsinn, C. (2000) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00270-0 · Cited by 7 · see citing works

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Fat tissue, aging, and cellular senescence
Tchkonia, T., Morbeck, D. E., Von Zglinicki, T., Van Deursen, J., Lustgarten, J., Scrable, H., Khosla, S., Jensen, M. D., & Kirkland, J. L. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00608.x · Cited by 1,094 · see citing works
Diabetes and mitochondrial function: Role of hyperglycemia and oxidative stress
Rolo, A. P., & Palmeira, C. M. (2006) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2006.01.003 · Cited by 1,007 · see citing works
Cardiac remodeling in obesity
Abel, E. D., Litwin, S. E., & Sweeney, G. (2008) · Physiological Reviews · doi:10.1152/physrev.00017.2007 · Cited by 736 · see citing works
Mitochondrial and cellular mechanisms for managing lipid excess
Aon, M. A., Bhatt, N., & Cortassa, S. C. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00282 · Cited by 253 · see citing works
Mitochondrial Uncoupling: A Key Contributor to Reduced Cardiac Efficiency in Diabetes
Boudina, S., & Abel, E. D. (2006) · Physiology · doi:10.1152/physiol.00008.2006 · Cited by 199 · see citing works
Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice
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“Diabetes impairs glucose uptake and results in an increase in fatty acid (FA) metabolism in cardiac tissue [3, 8, 9].”

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Abstract 17161: Inflammatory Serine Protease Inhibition Attenuates Myocyte Apoptosis and Cardiac Dysfunction via Intervention of Peroxisome Proliferator-activated Receptor Gamma-induced Lipotoxicity and Inflammation in High Fat Diet-induced Diabetic Cardiomyopathy
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Authors: Carley, A. N., & Severson, D. L.
Affiliations: University of Calgary (CA)
Corresponding author: Severson, David L.
ORCID: Carley, Andrew N.
Venue: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Publisher: Elsevier BV
Published: 2005-05
Volume: 1734
Issue: 2
Pages: 112-126
ISSN: 1388-1981 (ISSN-L)
DOI: 10.1016/j.bbalip.2005.03.005
OpenAlex: W2021871393
Cited by: 232
References: 166
Citations by year: 2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 7 · 2021: 12 · 2020: 1 · 2019: 7 · 2018: 10 · 2017: 9 · 2016: 11 · 2015: 16 · 2014: 21 · 2013: 13 · 2012: 16
FWCI: 2.59
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: type 2 diabetes, diabetic cardiomyopathy, cardiac fatty acid metabolism, fatty acid oxidation, triacylglycerol esterification, fatty acid uptake, mitochondrial uncoupling, uncoupling proteins, PPARα, lipotoxicity, cardiac contractile function, db/db mice, ob/ob mice, Zucker fatty rats, Zucker diabetic fatty rats
MeSH terms: Animals, Diabetes Mellitus, Type 2, Disease Models, Animal, Fatty Acids, Humans, Mice, Obese, Mitochondria, Myocardium, Obesity, Oxidation-Reduction, Rats, Zucker, Mice, Rats

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Fatty acid metabolism is enhanced in type 2 diabetic hearts

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