Cardiomyocyte-specific deletion of leptin receptors causes lethal heart failure in Cre-recombinase-mediated cardiotoxicity.

Although disruption of leptin signaling is associated with obesity as well as cardiac lipid accumulation and dysfunction, it has been difficult to separate the direct effects of leptin on the heart from those associated with the effects of leptin on body weight and fat mass. Using Cre-loxP recombinase technology, we developed tamoxifen-inducible, cardiomyocyte-specific leptin receptor-deficient mice to assess the role of leptin in regulating cardiac function. Cre recombinase activation in the heart resulted in transient reduction in left ventricular systolic function which recovered to normal levels by day 10. However, when cardiomyocyte leptin receptors were deleted in the setting of Cre recombinase-induced left ventricular dysfunction, irreversible lethal heart failure was observed in less than 10 days in all mice. Heart failure after leptin receptor deletion was associated with marked decreases of cardiac mitochondrial ATP, phosphorylated mammalian target of rapamycin (mTOR), and AMP-activated kinase (pAMPK). Our results demonstrate that specific deletion of cardiomyocyte leptin receptors, in the presence of increased Cre recombinase expression, causes lethal heart failure associated with decreased cardiac energy production. These observations indicate that leptin plays an important role in regulating cardiac function in the setting of cardiac stress caused by Cre-recombinase expression, likely through actions on cardiomyocyte energy metabolism.

[1]  C. O'Donnell,et al.  Restoration of glucose metabolism in leptin-resistant mouse hearts after acute myocardial infarction through the activation of survival kinase pathways. , 2012, Journal of molecular and cellular cardiology.

[2]  P. Schulze,et al.  Dynamics in insulin resistance and plasma levels of adipokines in patients with acute decompensated and chronic stable heart failure. , 2011, Journal of cardiac failure.

[3]  Michael E. Hall,et al.  Systolic dysfunction in cardiac-specific ligand-inducible MerCreMer transgenic mice. , 2011, American journal of physiology. Heart and circulatory physiology.

[4]  E. Abel,et al.  Central Leptin Signaling Is Required to Normalize Myocardial Fatty Acid Oxidation Rates in Caloric-Restricted ob/ob Mice , 2011, Diabetes.

[5]  S. Okamoto,et al.  Distinct Effects of Leptin and a Melanocortin Receptor Agonist Injected Into Medial Hypothalamic Nuclei on Glucose Uptake in Peripheral Tissues , 2009, Diabetes.

[6]  C. McTiernan,et al.  Leptin attenuates cardiac apoptosis after chronic ischaemic injury. , 2009, Cardiovascular research.

[7]  Y. Pinto,et al.  Avoidance of Transient Cardiomyopathy in Cardiomyocyte-Targeted Tamoxifen-Induced MerCreMer Gene Deletion Models , 2009, Circulation research.

[8]  Y. Pinto,et al.  Conditional Dicer Gene Deletion in the Postnatal Myocardium Provokes Spontaneous Cardiac Remodeling , 2008, Circulation.

[9]  N. Bodyak,et al.  Deletion of Ptpn11 (Shp2) in Cardiomyocytes Causes Dilated Cardiomyopathy via Effects on the Extracellular Signal–Regulated Kinase/Mitogen-Activated Protein Kinase and RhoA Signaling Pathways , 2008, Circulation.

[10]  H. Castro-Faria-Neto,et al.  Leptin Induces Macrophage Lipid Body Formation by a Phosphatidylinositol 3-Kinase- and Mammalian Target of Rapamycin-dependent Mechanism* , 2008, Journal of Biological Chemistry.

[11]  R. Roberts.  Faculty Opinions recommendation of mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. , 2007 .

[12]  V. Mootha,et al.  mTOR controls mitochondrial oxidative function through a YY1–PGC-1α transcriptional complex , 2007, Nature.

[13]  D. Carling.  The role of the AMP-activated protein kinase in the regulation of energy homeostasis. , 2007, Novartis Foundation symposium.

[14]  H. Taegtmeyer,et al.  Glucose phosphorylation is required for insulin-dependent mTOR signalling in the heart. , 2007, Cardiovascular research.

[15]  G. Lopaschuk,et al.  Cardiac Energy Metabolism in Obesity , 2007, Circulation research.

[16]  J. Calbet,et al.  Leptin receptors in human skeletal muscle , 2007, Journal of applied physiology.

[17]  N. Dalton,et al.  Inducible Cardiac-Restricted Expression of Enteroviral Protease 2A Is Sufficient to Induce Dilated Cardiomyopathy , 2006, Circulation.

[18]  S. Homma,et al.  Acute lipoprotein lipase deletion in adult mice leads to dyslipidemia and cardiac dysfunction. , 2006, American journal of physiology. Endocrinology and metabolism.

[19]  A. Dart,et al.  Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis , 2006, Journal of hypertension.

[20]  M. Eguchi,et al.  Distinct effects of short- and long-term leptin treatment on glucose and fatty acid uptake and metabolism in HL-1 cardiomyocytes. , 2006, Metabolism: clinical and experimental.

[21]  W. Pu,et al.  Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase. , 2006, Journal of cardiac failure.

[22]  Jun Ren,et al.  Leptin Regulates Cardiomyocyte Contractile Function Through Endothelin-1 Receptor–NADPH Oxidase Pathway , 2006, Hypertension.

[23]  A. Phan,et al.  Cardiac Myocyte Apoptosis Is Associated With Increased DNA Damage and Decreased Survival in Murine Models of Obesity , 2005, Circulation research.

[24]  Richard B Devereux,et al.  Recommendations for chamber quantification: a report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardio , 2005, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[25]  J. Molkentin,et al.  Temporally Controlled Onset of Dilated Cardiomyopathy Through Disruption of the SRF Gene in Adult Heart , 2005, Circulation.

[26]  G. Morley,et al.  Cardiac-Specific Loss of N-Cadherin Leads to Alteration in Connexins With Conduction Slowing and Arrhythmogenesis , 2005, Circulation research.

[27]  L. Turcotte,et al.  Short-term leptin treatment increases fatty acids uptake and oxidation in muscle of high fat-fed rats. , 2005, Metabolism: clinical and experimental.

[28]  G. Paolisso,et al.  Circulating leptin correlates with left ventricular mass in morbid (grade III) obesity before and after weight loss induced by bariatric surgery: a potential role for leptin in mediating human left ventricular hypertrophy. , 2005, The Journal of clinical endocrinology and metabolism.

[29]  R. Unger.  Hyperleptinemia: protecting the heart from lipid overload. , 2005, Hypertension.

[30]  B. Lorell,et al.  Mechanisms for Increased Glycolysis in the Hypertrophied Rat Heart , 2004, Hypertension.

[31]  N. Sonenberg,et al.  Upstream and downstream of mTOR. , 2004, Genes & development.

[32]  S. Izumo,et al.  Inhibition of mTOR Signaling With Rapamycin Regresses Established Cardiac Hypertrophy Induced by Pressure Overload , 2004, Circulation.

[33]  D. Carling,et al.  AMP-activated Protein Kinase Plays a Role in the Control of Food Intake* , 2004, Journal of Biological Chemistry.

[34]  C. Leeuwenburgh,et al.  Method for measuring ATP production in isolated mitochondria: ATP production in brain and liver mitochondria of Fischer-344 rats with age and caloric restriction. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[35]  S. S. Zhang,et al.  Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  H. Häring,et al.  Insulin-like effect of low-dose leptin on glucose transport in Langendorff rat hearts. , 2003, Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association.

[37]  G. Lopaschuk,et al.  Leptin Activates Cardiac Fatty Acid Oxidation Independent of Changes in the AMP-activated Protein Kinase-Acetyl-CoA Carboxylase-Malonyl-CoA Axis* , 2002, The Journal of Biological Chemistry.

[38]  Young-Bum Kim,et al.  Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature.

[39]  A. Jaeschke,et al.  Mammalian TOR: A Homeostatic ATP Sensor , 2001, Science.

[40]  J. Friedman,et al.  Selective deletion of leptin receptor in neurons leads to obesity. , 2001, The Journal of clinical investigation.

[41]  A. Berns,et al.  Growth inhibition and DNA damage induced by Cre recombinase in mammalian cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Crackower,et al.  Temporally Regulated and Tissue-Specific Gene Manipulations in the Adult and Embryonic Heart Using a Tamoxifen-Inducible Cre Protein , 2001, Circulation research.

[43]  R. Davisson,et al.  Long-term telemetric measurement of cardiovascular parameters in awake mice: a physiological genomics tool. , 2001, Physiological genomics.

[44]  Y. Minokoshi,et al.  Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle. , 2001, Biochemical Society transactions.

[45]  M. Nahata,et al.  Cardiotoxicity of Chemotherapeutic Agents , 2000 .

[46]  R. Burcelin,et al.  Acute stimulation of glucose metabolism in mice by leptin treatment , 1997, Nature.

[47]  C. McTiernan,et al.  Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice. , 2011, Cardiovascular research.

[48]  Cheuk-Kwan Sun,et al.  Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury. , 2008, Cardiovascular research.

[49]  B. Culver,et al.  Impaired cardiac contractile function in ventricular myocytes from leptin-deficient ob/ob obese mice. , 2006, The Journal of endocrinology.

[50]  M. Nahata,et al.  Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. , 2000, Drug safety.