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Reduced Mitochondrial Oxidative Capacity and Increased Mitochondrial Uncoupling Impair Myocardial Energetics in Obesity
Abstract
Background— Obesity is a risk factor for cardiovascular disease and is strongly associated with insulin resistance and type 2 diabetes. Recent studies in obese humans and animals demonstrated increased myocardial oxygen consumption (MV̇ o 2 ) and reduced cardiac efficiency (CE); however, the underlying mechanisms remain unclear. The present study was performed to determine whether mitochondrial dysfunction and uncoupling are responsible for reduced cardiac performance and efficiency in ob/ob mice. Methods and Results— Cardiac function, MV̇ o 2 , mitochondrial respiration, and ATP synthesis were measured in 9-week-old ob/ob and control mouse hearts. Contractile function and MV̇ o 2 in glucose-perfused ob/ob hearts were similar to controls under basal conditions but were reduced under high workload. Perfusion of ob/ob hearts with glucose and palmitate increased MV̇ o 2 and reduced CE by 23% under basal conditions, and CE remained impaired at high workload. In glucose-perfused ob/ob hearts, mitochondrial state 3 respirations were reduced but ATP/O ratios were unchanged. In contrast, state 3 respiration rates were similar in ob/ob and control mitochondria from hearts perfused with palmitate and glucose, but ATP synthesis rates and ATP/O ratios were significantly reduced in ob/ob , which suggests increased mitochondrial uncoupling. Pyruvate dehydrogenase activity and protein levels of complexes I, III, and V were reduced in obese mice. Conclusions— These data indicate that reduced mitochondrial oxidative capacity may contribute to cardiac dysfunction in ob/ob mice. Moreover, fatty acid but not glucose-induced mitochondrial uncoupling reduces CE in obese mice by limiting ATP production and increasing MV̇ o 2 .
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“For example, while some groups have reported cardiac hypertrophy in hearts of young ob/ob mice (30, 34, 227), others have only observed this phenotype in older animals (23, 24).”
From Cardiac remodeling in obesity (2008) · cites this paper as [30]
In the citing paper
“In isovolumic ob/ob hearts, although cardiac performance was similar at low work loads, there was a significant reduction at increased work loads (30).”
From Cardiac remodeling in obesity (2008) · cites this paper as [30]
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“We and others previously reported that the reduced rate of mitochondrial respiration capacity contributes to impairment of mitochondrial function and cardiac function (Boudina et al., 2005; DeNicola et al., 2014).”
BackgroundAl‐Rasheed, N. M., Al-Rasheed, N. M., Hasan, I. H., Alamin, M. A., Al‐Ajmi, H. N., Mohamad, R. A., & Mahmoud, A. M. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/1092015 · Cited by 144
“Hyperglycemia promotes generation of ROS and RNS in the mitochondria [49], and increased cardiac FAs activate NADPH oxidases and induce leakage of the mitochondrial electron transport chain [7].”
BackgroundNew insights into insulin resistance in the diabetic heart
Gray, S., & Kim, J. K. (2011) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2011.05.001 · Cited by 147
“Cardiac abnormality in obese mice is also associated with a reduction in mitochondrial oxidative capacity and increased mitochondrial uncoupling, an event that raises mitochondrial O2 consumption without parallel increases in energetics [72].”
Manifestations and mechanisms of myocardial lipotoxicity in obesity
Sletten, A. C., Peterson, L. R., & Schaffer, J. E. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12728 · Cited by 148
Mitochondrial Morphology in Metabolic Diseases
Galloway, C. A., & Yoon, Y. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4779 · Cited by 143
“In all models tested, except Akita mice where oxidative stress was not observed, cardiac and mitochondrial functions were decreased (9, 10, 16, 18, 19, 41, 53, 73, 80, 96, 122, 123), and these decreases were associated with increases in oxidative stress (10, 125, 142, 143).”
Cardiac metabolism in HFpEF: from fuel to signalling
Capone, F., Sotomayor-Flores, C., Bode, D., Wang, R., Rodolico, D., Strocchi, S., & Schiattarella, G. G. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvac166 · Cited by 145
O'Neill, B. T., Kim, J., Wende, A. R., Theobald, H. A., Tuinei, J., Buchanan, J., Guo, A., Zaha, V. G., Davis, D. K., Schell, J. C., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.09.001 · Cited by 137
“Metabolism 6, 294–306, October 2007 ª2007 Elsevier Inc. 303 Citrate Synthase CS activity was determined spectrophotometrically using whole heart or mixed gastrocnemius muscle homogenates as described previously (Boudina et al., 2005; Clark and Rodnick, 1998; Rodnick and Sidell, 1997).”
MethodInfluentialSelf-citationIlkun, O. L., & Boudina, S. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319270003 · Cited by 138
Self-citationCardiac fatty acid oxidation in heart failure associated with obesity and diabetes
Fukushima, A., & Lopaschuk, G. D. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.03.020 · Cited by 140
Mitochondrial Dynamics in Diabetic Cardiomyopathy
Galloway, C. A., & Yoon, Y. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6293 · Cited by 135
“Increased fatty acid oxidation coupled with decreased cardiac performance is symptomatic of mitochondrial dysfunction, which is likely respiration uncoupling based on an increased activity of uncoupling proteins (UCP2 or UCP3) observed in this model (14, 15).”
BackgroundInfluentialMitochondrial Mechanisms in Diabetic Cardiomyopathy
Gollmer, J., Zirlik, A., & Bugger, H. (2020) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2019.0185 · Cited by 139
Production of Reactive Oxygen Species in the Diabetic Heart
Teshima, Y., Takahashi, N., Nishio, S., Saito, S., Kondo, H., Fukui, A., Aoki, K., Yufu, K., Nakagawa, M., & Saikawa, T. (2013) · Circulation Journal · doi:10.1253/circj.cj-13-1187 · Cited by 134
Sverdlov, A. L., Elezaby, A., Qin, F., Behring, J. B., Luptak, I., Calamaras, T. D., Siwik, D. A., Miller, E. J., Liesa, M., Shirihai, O. S., et al. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002555 · Cited by 135
Diabetes, Oxidative Stress, Nitric Oxide and Mitochondria Function
Friederich, M., Hansell, P., & Palm, F. (2009) · Current Diabetes Reviews · doi:10.2174/157339909788166800 · Cited by 128
Mitochondrial oxidative metabolism and uncoupling proteins in the failing heart
Akhmedov, A. T., Rybin, V. O., & Marín-García, J. (2014) · Heart Failure Reviews · doi:10.1007/s10741-014-9457-4 · Cited by 128
“In contrast to UCP1 present predominantly in BAT, highly homologous UCP2, found in various mammalian tissues, and UCP3 are expressed in the mammalian myocardium [237, 238, 240, 242, 312–314].”
BackgroundCardiac, skeletal, and smooth muscle mitochondrial respiration: are all mitochondria created equal?
Park, S., Gifford, J. R., Andtbacka, R. H. I., Trinity, J. D., Hyngstrom, J. R., Garten, R. S., Diakos, N., Ives, S. J., Dela, F., Larsen, S., et al. (2014) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00227.2014 · Cited by 137
“Interestingly, although mitochondrial respiration of both cardiac and skeletal muscles has been studied extensively in health and disease (4, 5, 31, 32, 39), little is known about smooth muscle mitochondrial respiration (42).”
BackgroundDNA-PK Promotes the Mitochondrial, Metabolic, and Physical Decline that Occurs During Aging
Park, S. J., Gavrilova, O., Brown, A. L., Soto, J. E., Bremner, S. N., Kim, J., Xu, X., Yang, S., Um, J.-H., Koch, L. G., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.008 · Cited by 123
Self-citationMetabolic dysfunction in diabetic cardiomyopathy
Isfort, M. C., Stevens, S. C. W., Schaffer, S. W., Jong, C. J., & Wold, L. E. (2013) · Heart Failure Reviews · doi:10.1007/s10741-013-9377-8 · Cited by 128
Ježek, P., Holendová, B., Garlid, K., & Jabůrek, M. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7225 · Cited by 131
“Concerning the cardiac remodeling in the early stages of heart pathology, a compensation is developed as a slightly increased FA b-oxidation, followed by OXPHOS decline as glucose uptake and glycolysis are upregulated during the pathology progression (131, 229, 249), specifically in obesity (40).”
BackgroundAdaptation and maladaptation of the heart in obesity
Harmancey, R., Wilson, C. R., & Taegtmeyer, H. (2008) · Hypertension · doi:10.1161/hypertensionaha.108.110031 · Cited by 121
Duncan, J. G., Bharadwaj, K. G., Fong, J. L., Mitra, R., Sambandam, N., COURTOIS, M. R., Lavine, K. J., Goldberg, I. J., & Kelly, D. P. (2010) · Circulation · doi:10.1161/circulationaha.109.888735 · Cited by 126
Rovira‐Llopis, S., Apostolova, N., Bañuls, C., Muntané, J., Rocha, M., & Víctor, V. M. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7313 · Cited by 125
“Cardiac efficiency is reduced in insulin-resistant animal models, such as ob/ob mice, in which high levels of FFAs reduce mitochondrial oxidative capacity and limit ATP synthesis (34).”
Wang, H., Bei, Y., Lu, Y., Sun, W., Liu, Q., Wang, Y., Cao, Y., Chen, P., Xiao, J., & Kong, X. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000374021 · Cited by 120
Schilling, J. D., & Mann, D. L. (2012) · Heart Failure Clinics · doi:10.1016/j.hfc.2012.06.007 · Cited by 120
An APPL1-AMPK signaling axis mediates beneficial metabolic effects of adiponectin in the heart
Fang, X., Palanivel, R., Cresser, J., Schram, K., Ganguly, R., Thong, F. S. L., Tuinei, J., Xu, A., Abel, E. D., & Sweeney, G. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00086.2010 · Cited by 119
“To prepare homogenates for Western analyses, perfused hearts were flash frozen, pulverized under liquid nitrogen and then processed as described previously (5), with slight modifications.”
MethodSelf-citationEffects of Palmitate on Ca2+ Handling in Adult Control and ob/ob Cardiomyocytes
Fauconnier, J., Andersson, D. C., Zhang, S., Lanner, J. T., Wibom, R., Katz, A., Bruton, J. D., & Westerblad, H. (2007) · Diabetes · doi:10.2337/db06-0739 · Cited by 116
Insulin receptor substrate signaling suppresses neonatal autophagy in the heart
Riehle, C., Wende, A. R., Sena, S., Pires, K. M., Pereira, R. O., Zhu, Y., Bugger, H., Frank, D., Bevins, J., Chen, D., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci71171 · Cited by 114
“ity were determined as previously described (56) using a Synergy HT”
Self-citationHafstad, A. D., Lund, J., Hadler‐Olsen, E., Höper, A. C., Larsen, T. S., & Aasum, E. (2013) · Diabetes · doi:10.2337/db12-1580 · Cited by 116
“Several obesity- or diabetes-induced changes, including increased fatty acid oxidation (4,8,9), impaired calcium handing (10,11), increased oxidative stress (12), and mitochondrial dysfunction (13), are factors that, most likely, contribute to increased MVO2.”
BackgroundThe role of mitochondria in the aetiology of insulin resistance and type 2 diabetes
Martin, S. D., & McGee, S. L. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.09.019 · Cited by 117
Chronic Inhibition of Pyruvate Dehydrogenase in Heart Triggers an Adaptive Metabolic Response
Chambers, K. T., Leone, T. C., Sambandam, N., Kovács, A. D., Wagg, C. S., Lopaschuk, G. D., Finck, B. N., & Kelly, D. P. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.217349 · Cited by 109
Metadata
- Authors
- Boudina, S., Sena, S., O’Neill, B. T., Tathireddy, P., Young, M. E., & Abel, E. D.
- Affiliations
- Baylor College of Medicine (US)
- From the Division of Endocrinology, Metabolism and Diabetes and Program in Human Molecular Biology and Genetics (S.B., S.S., B.T.O., P.T., E.D.A.), University of Utah School of Medicine, Salt Lake City, Utah, and USDA/ARS Children’s Nutrition Research Center and Department of Pediatrics (M.E.Y.), Baylor College of Medicine, Houston, Tex.
- Venue
- Circulation
- Published
- 2005-10-25
- Volume
- 112
- Issue
- 17
- Pages
- 2686-2695
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2160331251
- Cited by
- 502
- References
- 31
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 20 · 2023: 17 · 2022: 22 · 2021: 23 · 2020: 23 · 2019: 16 · 2018: 20 · 2017: 29 · 2016: 25 · 2015: 42 · 2014: 48 · 2013: 39 · 2012: 33
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-12-06)
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL073167, R01-HL-73167, UO1HL70525, U01HL070525)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK092065)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- obesity, mitochondrial uncoupling, mitochondrial oxidative capacity, myocardial oxygen consumption, cardiac efficiency, cardiac energetics, ob/ob mice, palmitate, fatty acid metabolism, pyruvate dehydrogenase, mitochondrial respiration, ATP production, insulin resistance, type 2 diabetes, cardiac contractile function
- MeSH terms
- Adenosine Triphosphate, Animals, Energy Metabolism, Mice, Inbred C57BL, Mice, Obese, Mitochondria, Heart, Myocardium, Obesity, Oxidative Phosphorylation, Oxygen Consumption, Mice
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