Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK
Abstract
New Findings What is the central question of the study? Is the reduced signalling of AMP‐activated protein kinase (AMPK), a key regulator of energy homeostasis in the heart, responsible for the reduced β‐adrenergic responsiveness of the heart in obesity? What is the main finding and its importance? Inhibition of AMPK in isolated hearts prevented the reduced cardiac β‐adrenergic responsiveness of obese rats, which was accompanied by reduced phosphorylation of AMPK, a proxy of AMPK activity. This suggests a direct functional link between β‐adrenergic responsiveness and AMPK signalling in the heart, and it suggests that AMPK might be an important target to restore the β‐adrenergic responsiveness in the heart in obesity. Abstract The obesity epidemic impacts heavily on cardiovascular health, in part owing to changes in cardiac metabolism. AMP‐activated protein kinase (AMPK) is a key regulator of energy homeostasis in the heart and is regulated by β‐adrenoceptors (β‐ARs) in normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac β‐AR responsiveness, although it is unclear whether AMPK signalling, downstream of β‐ARs, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced β‐AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested β‐AR responsiveness to the β1‐AR agonist isoprenaline (ISO, 1 × 10−10to 5 × 10−8 m) in the absence and presence of the AMPK inhibitor, compound C (CC, 10 μm). The β1‐AR expression and AMPK phosphorylation were assessed by Western blot. β‐Adrenergic responsiveness was reduced in the hearts of obese rats (logEC50of ISO‐developed pressure dose–response curves: lean −8.53 ± 0.13 × 10x m versusobese −8.35 ± 0.10 × 10x m;P < 0.05 leanversusobese,n = 6 per group). This difference was not apparent after AMPK inhibition (logEC50of ISO‐developed pressure curves: lean CC −8.19 ± 0.12 × 10x m versusobese CC 8.17 ± 0.13 × 10x m,P < 0.05,n = 6 per group). β1‐Adrenergic receptor expression and AMPK phosphorylation were reduced in hearts of obese rats (AMPK at Thr172: lean 1.73 ± 0.17 a.u. versuslean CC 0.81 ± 0.13 a.u., and obese 1.18 ± 0.09 a.u. versusobese CC 0.81 ± 0.16 a.u.,P < 0.05,n = 6 per group). Thus, a direct functional link between β‐adrenergic responsiveness and AMPK signalling in the heart exists, and AMPK might be an important target to restore the reduced cardiac β‐adrenergic responsiveness in obesity.
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A direct functional connection between AMPK signaling and β-adrenergic responsiveness exists in the heart, and AMPK might be a valuable target to recover the decreased β-adrenergic responsive in the heart of obesity.
“A direct functional connection between AMPK signaling and β-adrenergic responsiveness exists in the heart, and AMPK might be a valuable target to recover the decreased β-adrenergic responsive in the heart of obesity [270].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [270]
Cites
Hypertension and Antihypertensive Therapy as Risk Factors for Type 2 Diabetes Mellitus
Gress, T. W., Nieto, F. J., Shahar, E., Wofford, M. R., & Brancati, F. L. (2000) · New England Journal of Medicine · doi:10.1056/nejm200003303421301 · Cited by 1,202 · see citing works
Leptin receptor missense mutation in the fatty Zucker rat
Phillips, M. S., Liu, Q., Hammond, H. A., Dugan, V., Hey, P. J., Caskey, C. T., & Hess, J. F. (1996) · Nature Genetics · doi:10.1038/ng0596-18 · Cited by 822 · see citing works
AMP-Activated Protein Kinase – Development of the Energy Sensor Concept
Hardie, D. G., Hawley, S. A., & Scott, J. W. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.108944 · Cited by 813 · see citing works
Lambert, G. W., Straznicky, N. E., Lambert, É., Dixon, J. B., & Schlaich, M. P. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.02.002 · Cited by 345 · see citing works
Hypothesis: β-Adrenergic Receptor Blockers and Weight Gain
Sharma, A. M., Pischon, T., Hardt, S., Kunz, I., & Luft, F. C. (2001) · Hypertension · doi:10.1161/01.hyp.37.2.250 · Cited by 339 · see citing works
Impact of Type 2 Diabetes Mellitus on Sympathetic Neural Mechanisms in Hypertension
Huggett, R. J., Scott, E. M., Gilbey, S. G., Stoker, J. B., Mackintosh, A. F., & Mary, D. A. S. G. (2003) · Circulation · doi:10.1161/01.cir.0000103123.66264.fe · Cited by 305 · see citing works
Phenotype of fatty Due to Gln269Pro Mutation in the Leptin Receptor (Lepr)
Chua, S. C., White, D. W., Wu-Peng, X. S., Liu, S.-M., Okada, N. A., Kershaw, E. E., Chung, W. K., Power-Kehoe, L., Chua, M., Tartaglia, L. A., et al. (1996) · Diabetes · doi:10.2337/diab.45.8.1141 · Cited by 292 · see citing works
CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK
Watt, M. J., Dzamko, N. L., Thomas, W. G., Rose‐John, S., Ernst, M., Carling, D., Kemp, B. E., Febbraio, M. A., & Steinberg, G. R. (2006) · Nature Medicine · doi:10.1038/nm1383 · Cited by 275 · see citing works
Biology of Obesity: Lessons from Animal Models of Obesity
Kanasaki, K., & Koya, D. (2011) · BioMed Research International · doi:10.1155/2011/197636 · Cited by 174 · see citing works
The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts
Dinçer, Ü. D., Bidasee, K. R., Güner, Ş., Tay, A., Ozcelikay, A. T., & ALTAN, V. M. (2001) · Diabetes · doi:10.2337/diabetes.50.2.455 · Cited by 172 · see citing works
Ko, H. J., Zhang, Z., Jung, D. Y., Jun, J. Y., Ma, Z., Jones, K. E., Chan, S. Y., & Kim, J. K. (2009) · Diabetes · doi:10.2337/db08-1361 · Cited by 157 · see citing works
Regulation of Adrenergic Receptor Function by Phosphorylation
Lefkowitz, R. J., & Caron, M. G. (1986) · Current topics in cellular regulation · doi:10.1016/b978-0-12-152828-7.50007-x · Cited by 143 · see citing works
Lindholm, C. R., Ertel, R. L., Bauwens, J. D., Schmuck, E. G., Mulligan, J. D., & Saupe, K. W. (2013) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-012-0199-2 · Cited by 136 · see citing works
Zhuo, X., Wu, Y., Ni, Y.-J., Liu, J.-H., Gong, M., Wang, X.-H., Feng, W., Wang, T., Yuan, Z., Ma, A.-Q., et al. (2013) · APOPTOSIS · doi:10.1007/s10495-013-0843-5 · Cited by 121 · see citing works
Role of PP2C in cardiac lipid accumulation in obese rodents and its prevention by troglitazone
Wang, M.-Y., & Unger, R. H. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00004.2004 · Cited by 100 · see citing works
Lamberts, R. R., Onderwater, G., Hamdani, N., Vreden, M. J. A., Steenhuisen, J., Eringa, E. C., Loer, S. A., Stienen, G. J. M., & Bouwman, R. A. (2009) · Circulation · doi:10.1161/circulationaha.108.828426 · Cited by 93 · see citing works
Self-citationAMP-activated protein kinase conducts the ischemic stress response orchestra
Young, L. H. (2008) · Circulation · doi:10.1161/circulationaha.107.713115 · Cited by 82 · see citing works
Daniels, A., van Bilsen, M., Janssen, B. J., Brouns, A. E., Cleutjens, J. P. M., Roemen, T. H. M., Schaart, G., van der Velden, J., Vusse, G. J., & van Nieuwenhoven, F. A. (2010) · Acta Physiologica · doi:10.1111/j.1748-1716.2010.02102.x · Cited by 78 · see citing works
Nixon, B. R., Thawornkaiwong, A., Jin, J., Brundage, E. A., Little, S. C., Davis, J. P., Solaro, R. J., & Biesiadecki, B. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.323048 · Cited by 69 · see citing works
Agapitov, A. V., Correia, M., Sinkey, C. A., & Haynes, W. G. (2008) · Hypertension · doi:10.1161/hypertensionaha.107.109603 · Cited by 63 · see citing works
Lamberts, R. R., Lingam, S. J., Wang, H.-Y., Bollen, I. A., Hughes, G., Galvin, I. F., Bunton, R. W., Bahn, A., Katare, R., Baldi, J., et al. (2014) · Cardiovascular Diabetology · doi:10.1186/1475-2840-13-72 · Cited by 60 · see citing works
Self-citationMinhas, K. M., Khan, S. A., Raju, S. V. Y., Phan, A. C., Gonzalez, D. R., Skaf, M. W., Lee, K., Tejani, A. D., Saliaris, A. P., Barouch, L. A., et al. (2005) · The Journal of Physiology · doi:10.1113/jphysiol.2005.084566 · Cited by 59 · see citing works
Reduced Cardiac Contractile Responsiveness to Isoproterenol in Obese Rabbits
Carroll, J. F., Jones, A. E., Hester, R. L., Reinhart, G. A., Cockrell, K. L., & Mizelle, H. L. (1997) · Hypertension · doi:10.1161/01.hyp.30.6.1376 · Cited by 53 · see citing works
Moberly, S. P., Mather, K. J., Berwick, Z. C., Owen, M. K., Goodwill, A. G., Casalini, E. D., Hutchins, G. D., Green, M. A., Ng, Y., Considine, R. V., et al. (2013) · Basic Research in Cardiology · doi:10.1007/s00395-013-0365-x · Cited by 51 · see citing works
Schouten, V. J. A., Allaart, C. P., & Westerhof, N. (1992) · The Journal of Physiology · doi:10.1113/jphysiol.1992.sp019180 · Cited by 49 · see citing works
Refeeding hypertension in obese spontaneously hypertensive rats.
Ernsberger, P. R., Koletsky, R. J., Baskin, J. S., & Foley, M. (1994) · Hypertension · doi:10.1161/01.hyp.24.6.699 · Cited by 47 · see citing works
Effects of pioglitazone on cardiac and adipose tissue pathology in rats with metabolic syndrome
Matsuura, N., Asano, C., Nagasawa, K., Ito, S., Sano, Y., Minagawa, Y., Yamada, Y., Hattori, T., Watanabe, S., Murohara, T., et al. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.11.099 · Cited by 45 · see citing works
Thaung, H. P. A., Baldi, J. C., Wang, H.-Y., Hughes, G., Cook, R. F., Bussey, C. T., Sheard, P. W., Bahn, A., Jones, P. P., Schwenke, D. O., et al. (2015) · Diabetes · doi:10.2337/db14-0955 · Cited by 45 · see citing works
Self-citationSherwood, A., Hill, L. K., Blumenthal, J. A., Johnson, K. S., & Hinderliter, A. L. (2017) · Journal of Hypertension · doi:10.1097/hjh.0000000000001266 · Cited by 36 · see citing works
Hohl, C. M., Hu, B., Fertel, R. H., Russell, J. C., McCune, S. A., & Altschuld, R. A. (1993) · Cardiovascular Research · doi:10.1093/cvr/27.2.238 · Cited by 35 · see citing works
The effects of diabetes on β-adrenoceptor mediated responsiveness of human and rat atria
Dinçer, Ü. D., Onay-Beşi̇kçi̇, A., Arı, N., Ozcelikay, A. T., & ALTAN, V. M. (1998) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(98)00034-5 · Cited by 34 · see citing works
Ferron, A. J. T., Jacobsen, B. B., Sant’Ana, P. G., de Campos, D. H. S., de Tomasi, L. C., Luvizotto, R. D. A. M., Cicogna, A. C., Leopoldo, A. S., & Lima‐Leopoldo, A. P. (2015) · PLoS ONE · doi:10.1371/journal.pone.0138605 · Cited by 34 · see citing works
β2- but not β1-adrenoceptor activation modulates intracellular oxygen availability
Li, J., Yan, B., Huo, Z., Liu, Y., Xu, J., Sun, Y., Liu, Y., Liang, D., Peng, L., Zhang, Y., et al. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.190900 · Cited by 33 · see citing works
An, D., Kewalramani, G., Qi, D., Pulinilkunnil, T., Ghosh, S., Abrahani, A., Wambolt, R., Allard, M. F., Innis, S. M., & Rodrigues, B. B. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00588.2004 · Cited by 30 · see citing works
Disfunção miocárdica e alterações no trânsito de cálcio intracelular em ratos obesos
Lima‐Leopoldo, A. P., Leopoldo, A. S., Sugizaki, M. M., Bruno, A., do Nascimento, A. F., Luvizotto, R. D. A. M., de Oliveira-Junior, S. A., Castardeli, É., Padovani, C. R., & Cicogna, A. C. (2011) · Arquivos Brasileiros de Cardiologia · doi:10.1590/s0066-782x2011005000061 · Cited by 28 · see citing works
Regulation of cardiac adenylate cyclase activity in rodent models of obesity
Strassheim, D., Houslay, M. D., & Milligan, G. (1992) · Biochemical Journal · doi:10.1042/bj2830203 · Cited by 24 · see citing works
Chatelain, P., Robberecht, P., NEEF, P. D., Camus, J., Poloczek, P., & Christophe, J. (1981) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/bf00582704 · Cited by 24 · see citing works
Jiang, C., Carillion, A., Na, N., JONG, A. D., Feldman, S. F., Lacorte, J., Bonnefont‐Rousselot, D., Riou, B., & Amour, J. (2015) · Critical Care Medicine · doi:10.1097/ccm.0000000000000999 · Cited by 24 · see citing works
alpha1-adrenergic receptors activate AMP-activated protein kinase in rat hearts.
Xu, M., Zhao, Y. T., Song, Y., Hao, T.-P., Lu, Z., Han, Q., Wang, S., & Zhang, Y. Y. (2007) · PubMed · Cited by 21 · see citing works
Vileigas, D. F., de Deus, A. F., da Silva, D. C. T., de Tomasi, L. C., de Campos, D. H. S., Adorni, C. S., de Oliveira, S. M., Sant’Ana, P. G., Okoshi, K., Padovani, C. R., et al. (2016) · Physiological Reports · doi:10.14814/phy2.12914 · Cited by 21 · see citing works
β-Adrenoceptor density and adenylyl cyclase activity in obese rabbit hearts
Carroll, J., Kyser, C., & Martin, M. S. (2002) · International Journal of Obesity · doi:10.1038/sj.ijo.0801957 · Cited by 20 · see citing works
Pérez‐Schindler, J., Philp, A., Baar, K., & Hernández-Cascales, J. (2011) · Life Sciences · doi:10.1016/j.lfs.2011.03.020 · Cited by 19 · see citing works
The Role of Sympatho-Inhibition in Combination Treatment of Obesity-Related Hypertension
Carnagarin, R., Gregory, C., Azzam, O., Hillis, G. S., Schultz, C. J., Watts, G. F., Bell, D. A., Matthews, V. B., & Schlaich, M. P. (2017) · Current Hypertension Reports · doi:10.1007/s11906-017-0795-1 · Cited by 17 · see citing works
Effect of bupivacaine on sevoflurane-induced preconditioning in isolated rat hearts
Bouwman, R. A., Vreden, M. J. A., Hamdani, N., Wassenaar, L. E. J., Smeding, L. S., Loer, S. A., Stienen, G. J. M., & Lamberts, R. R. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.08.014 · Cited by 16 · see citing works
Self-citationBussey, C. T., de Leeuw, A. E., & Lamberts, R. R. (2014) · Cardiovascular Diabetology · doi:10.1186/s12933-014-0161-4 · Cited by 14 · see citing works
Self-citationCai, H., Zhang, G., Chen, W.-J., Zhang, B., Zhang, J., Chang, J.-R., Tang, C., Qi, Y., & Yin, X. (2014) · Die Pharmazie · doi:10.31083/ph.2014.3663 · Cited by 10 · see citing works
Thaung, H. P. A., Yao, Y., Bussey, C. T., Hughes, G., Jones, P. P., Bahn, A., Sammut, I. A., & Lamberts, R. R. (2015) · Experimental Physiology · doi:10.1113/ep085021 · Cited by 10 · see citing works
Self-citationDecreased beta-adrenergic receptor binding in obese female zucker rats
Bass, S., & Ritter, S. (1985) · Journal of the Autonomic Nervous System · doi:10.1016/0165-1838(85)90127-4 · Cited by 9 · see citing works
Cook, R. F., Bussey, C. T., Mellor, K. M., Cragg, P. A., & Lamberts, R. R. (2017) · Experimental Physiology · doi:10.1113/ep086293 · Cited by 9 · see citing works
Self-citationBuñag, R. D., Tomita, T., & Krizsan, D. (1990) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(25)12715-8 · Cited by 8 · see citing works
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- Authors
- Bussey, C. T., Thaung, H. P. A., Hughes, G., Bahn, A., & Lamberts, R. R.
- Affiliations
- University of Otago (NZ)
- Corresponding author
- Lamberts, Regis R.
- Venue
- Experimental Physiology
- Publisher
- Wiley
- Published
- 2018-06-29
- Volume
- 103
- Issue
- 8
- Pages
- 1067-1075
- ISSN
- 0958-0670 (ISSN-L)
- 1469-445X
- OpenAlex
- W2805924334
- Cited by
- 10
- References
- 50
- Citations by year
- 2026: 3 · 2025: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2
- FWCI
- 0.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Otago
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- responsiveness, AMPK, Zucker rats, isoproterenol, compound C, AMPK inhibition, cardiac hypertrophy, myocardial fibrosis, sympathetic hyperactivity, myocardial metabolism, obesity cardiomyopathy, AMPK phosphorylation, cardiac contractility
- MeSH terms
- Adrenergic beta-Agonists, Animals, Heart, Isoproterenol, Male, Myocardium, Obesity, Phosphorylation, Rats, Zucker, Signal Transduction, Rats, AMP-Activated Protein Kinases
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