Effects of Short Term Adiponectin Receptor Agonism on Cardiac Function and Energetics in Diabetic db/db Mice
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Objective: Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice. Methods: A non-selective adiponectin receptor agonist, AdipoRon, and vehicle were injected intraperitoneally into Eight-week-old db/db or C57BLKS/J mice for 10 days. Cardiac morphology and function were evaluated by echocardiography and working heart perfusions. Results: Based on echocardiography, AdipoRon treatment did not alter ejection fraction, left ventricular diameters or left ventricular wall thickness in db/db mice compared to vehicle-treated mice. In isolated working hearts, an impairment in cardiac output and efficiency in db/db mice was not improved by AdipoRon. Mitochondrial respiratory capacity, respiration in the presence of oligomycin, and 4-hydroxynonenal levels were similar among all groups. However, AdipoRon induced a marked shift in the substrate oxidation pattern in db/db mice towards increased reliance on glucose utilization. In parallel, the diabetes-associated increase in serum triglyceride levels in vehicle-treated db/db mice was blunted by AdipoRon treatment, while an increase in myocardial triglycerides in vehicle-treated db/db mice was not altered by AdipoRon treatment. Conclusion: AdipoRon treatment shifts myocardial substrate preference towards increased glucose utilization, likely by decreasing fatty acid delivery to the heart, but was not sufficient to improve cardiac output and efficiency in db/db mice.
Abstract
Objective: Impaired cardiac efficiency is a hallmark of diabetic cardiomyopathy in models of type 2 diabetes. Adiponectin receptor 1 (AdipoR1) deficiency impairs cardiac efficiency in non-diabetic mice, suggesting that hypoadiponectinemia in type 2 diabetes may contribute to impaired cardiac efficiency due to compromised AdipoR1 signaling. Thus, we investigated whether targeting cardiac adiponectin receptors may improve cardiac function and energetics, and attenuate diabetic cardiomyopathy in type 2 diabetic mice. Methods: A non-selective adiponectin receptor agonist, AdipoRon, and vehicle were injected intraperitoneally into Eight-week-old db/db or C57BLKS/J mice for 10 days. Cardiac morphology and function were evaluated by echocardiography and working heart perfusions. Results: Based on echocardiography, AdipoRon treatment did not alter ejection fraction, left ventricular diameters or left ventricular wall thickness in db/db mice compared to vehicle-treated mice. In isolated working hearts, an impairment in cardiac output and efficiency in db/db mice was not improved by AdipoRon. Mitochondrial respiratory capacity, respiration in the presence of oligomycin, and 4-hydroxynonenal levels were similar among all groups. However, AdipoRon induced a marked shift in the substrate oxidation pattern in db/db mice towards increased reliance on glucose utilization. In parallel, the diabetes-associated increase in serum triglyceride levels in vehicle-treated db/db mice was blunted by AdipoRon treatment, while an increase in myocardial triglycerides in vehicle-treated db/db mice was not altered by AdipoRon treatment. Conclusion: AdipoRon treatment shifts myocardial substrate preference towards increased glucose utilization, likely by decreasing fatty acid delivery to the heart, but was not sufficient to improve cardiac output and efficiency in db/db mice.
참고문헌 (47)
- Arita Y, "Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity", Biochem Biophys Res Commun, 257, pp.79~83 (1999)
- Hotta K, "Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients", Arterioscler Thromb Vasc Biol, 20, pp.1595~1599 (2000)
- Basu R, "Selective downregulation of the high molecular weight form of adiponectin in hyperinsulinemia and in type 2 diabetes : differential regulation from nondiabetic subjects", Diabetes, 56, pp.2174~2177 (2007)
- Fruebis J, "Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice", Proc Natl Acad Sci U S A, 98, pp.2005~2010 (2001)
- Yamauchi T, "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity", Nat Med, 7, pp.941~946 (2001)
- Berg AH, "The adipocyte-secreted protein Acrp30 enhances hepatic insulin action", Nat Med, 7, pp.947~953 (2001)
- Yamauchi T, "Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions", Nat Med, 13, pp.332~339 (2007)
- Iwabu M, "Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+)and AMPK", SIRT1, 2010, pp.464, 1313~1319
- Liao Y, "Exacerbation of heart failure in adiponectin-deficient mice due to impaired regulation of AMPK and glucose metabolism", Cardiovasc Res, 67, pp.705~713 (2005)
- Shibata R, "Adiponectin-mediated modulation of hypertrophic signals in the heart", Nat Med, 10, pp.1384~1389 (2004)
- Shibata R, "Adiponectin protects against myocardial ischemia-reperfusion injury through AMPK-and COX-2-dependent mechanisms", Nat Med, 11, pp.1096~1103 (2005)
- Tao L, "Adiponectin cardioprotection after myocardial ischemia", reperfusion involves the reduction of oxidative, Circulation, pp.2007, 115[DOI]
- Okada-Iwabu M, "A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity", Nature, 503, pp.493~499 (2013)
- Zhang N, "AdipoRon, an adiponectin receptor agonist, attenuates cardiac remodeling induced by pressure overload", J Mol Med(Berl), 96, pp.1345~1357 (2018)
- Zhang Y, "AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings", Am J Physiol Endocrinol Metab, 309, pp.E275~E282 (2015)
- Kim Y, "The adiponectin receptor agonist Adiporon ameliorates diabetic nephropathy in a model of type 2 diabetes", J Am Soc Nephrol, 29, pp.1108~1127 (2018)
- Choi SK, "AdipoRon, adiponectin receptor agonist, improves vascular function in the mesenteric arteries of type 2 diabetic mice", PLoS One, 15, pp.e0230227~ (2020)
- Mazumder PK, "Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob", ob mouse hearts, 2004, pp.53, 2366~2374
- Buchanan J, "Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity", Endocrinology, 146, pp.5341~5349 (2005)
- How OJ, "Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice", Diabetes, 55, pp.466~473 (2006)
- Boudina S, "Mitochondrial energetics in the heart in obesity-related diabetes : direct evidence for increased uncoupled respiration and activation of uncoupling proteins", Diabetes, 56, pp.2457~2466 (2007)
- Koentges C, "Myocardial mitochondrial dysfunction in mice lacking adiponectin receptor 1", Basic Res Cardiol, 110, pp.37~ (2015)
- Koentges C, "Gene expression analysis to identify mechanisms underlying heart failure susceptibility in mice and humans", Basic Res Cardiol, 113, pp.8~ (2017)
- Koentges C, "SIRT3 deficiency impairs mitochondrial and contractile function in the heart", Basic Res Cardiol, 110, pp.36~ (2015)
- Venardos K, "The PKD inhibitor CID755673 enhances cardiac function in diabetic db", db mice, 2015, pp.10, e0120934~
- Bugger H, "Rodent models of diabetic cardiomyopathy", Dis Model Mech, 2, pp.454~466 (2009)
- Qiao L, "Adiponectin reduces plasma triglyceride by increasing VLDL triglyceride catabolism", Diabetes, 57, pp.1824~1833 (2008)
- Carley AN, "Triacylglycerol turnover in the failing heart", Biochim Biophys Acta, 1861, pp.1492~1499 (2016)
- Christou GA, "Adiponectin and lipoprotein metabolism", Obes Rev, 14, pp.939~949 (2013)
- Zhou M, "Upregulation of UCP2 by adiponectin : the involvement of mitochondrial superoxide and hnRNP K", PLoS One, 7, pp.e32349~ (2012)
- Shibata S, "Adiponectin regulates cutaneous wound healing by promoting keratinocyte proliferation and migration via the ERK signaling pathway", J Immunol, 189, pp.3231~3241 (2012)
- Miyazaki T, "Adiponectin activates c-Jun NH2-terminal kinase and inhibits signal transducer and activator of transcription 3", Biochem Biophys Res Commun, 333, pp.79~87 (2005)
- Taegtmeyer H, "Linking gene expression to function : metabolic flexibility in the normal and diseased heart", Ann N Y Acad Sci, 1015, pp.202~213 (2004)
- Lopaschuk GD, "Myocardial fatty acid metabolism in health and disease", Physiol Rev, 90, pp.207~258 (2010)
- Randle PJ, "Mechanisms decreasing glucose oxidation in diabetes and starvation : role of lipid fuels and hormones", Diabetes Metab Rev, 4, pp.623~638 (1988)
- Hue L, "The Randle cycle revisited : a new head for an old hat", Am J Physiol Endocrinol Metab, 297, pp.E578~E591 (2009)
- Fragasso G, "A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure", J Am Coll Cardiol, 48, pp.992~998 (2006)
- Sabbah HN, "Ranolazine, a partial fatty acid oxidation(pFOX)inhibitor, improves left ventricular function in dogs with chronic heart failure", J Card Fail, 8, pp.416~422 (2002)
- Beadle RM, "Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy", JACC Heart Fail, 3, pp.202~211 (2015)
- Sossalla S, "Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts--role of late sodium current and intracellular ion accumulation", J Mol Cell Cardiol, 45, pp.32~43 (2008)
- Tsushima K, "Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission", Circ Res, 122, pp.58~73 (2018)
- Chiu HC, "A novel mouse model of lipotoxic cardiomyopathy", J Clin Invest, 107, pp.813~822 (2001)
- Schmitz FJ, "Improvement of myocardial function and metabolism in diabetic rats by the carnitine palmitoyl transferase inhibitor Etomoxir", Horm Metab Res, 27, pp.515~522 (1995)
- Reinauer H, "Influence of carnitine acyltransferase inhibitors on the performance and metabolism of rat cardiac muscle", J Clin Chem Clin Biochem, 28, pp.335~339 (1990)
- Hafstad AD, "Perfused hearts from type 2 diabetic(db", db)mice show metabolic responsiveness to insulin, 2006, pp.290, H1763~H1769
- Hafstad AD, "Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic(db", db)mice, 2007, pp.292, E1288~E1294
- Ramanathan T, "Glucose-insulin-potassium solution improves left ventricular energetics in chronic ovine diabetes", Ann Thorac Surg, 77, pp.1408~1414 (2004)