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

Abstract

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.

Importance of leptin signaling and signal transducer and activator of transcription-3 activation in mediating the cardiac hypertrophy associated with obesity

“…Our analyses also revealed significantly elevated numbers of apoptotic cells in hearts of obese LepR S1138 and LepR db/db mice, consistent with a reduced activation of STAT3-responsive anti-apoptotic genes [40]. Although findings in mice with systemic defects in leptin signal transduction may have been confounded by the concomitant presence of obesity and associated metabolic and inflammatory alterations, adverse cardiac remodeling after MI [42] or lethal heart failure [43] were recently reported in mice with cardiomyocyte-specific LepR deletion. On the other hand, the beneficial effects of leptin-mediated STAT3 activation may not be restricted to cardiomyocytes.…”

Rescue of cardiac leptin receptors indb/dbmice prevents myocardial triglyceride accumulation

“…Disruption of these leptin signaling pathways causes dilated cardiomyopathies (21,24,26). Previous studies from our laboratory and others have also demonstrated the protective role of leptin against the development of heart failure, and this appears to be mediated at least in part by cardiac metabolic effects (17,32). In the present study, we demonstrated significant increases in p-STAT3 and STAT3 in the hearts of db/db-cardiac LepR rescue mice compared with db/db mice and lean controls, indicative of increased leptin signaling in the hearts of these mice.…”

“…Echocardiographic assessment of cardiac function was conducted using a Vevo 770 High Resolution In Vivo Imaging System (Visualsonics, Toronto, ON, Canada), as described previously (16,17). Measurements were made with a 710B RMV scanhead with a center frequency of 25 MHz.…”

Beneficial effects of leptin treatment in a setting of cardiac dysfunction induced by transverse aortic constriction in mouse

“…Leptin signalling has been shown to have an important role in maintaining ATP formation because knockout of leptin in stressed mice is lethal (Hall et al . ). Thus, in the setting of HF, leptin may help, amongst other plausible mechanisms, to refill the SR with Ca 2+ , providing ATP to the SERCA pump or by increasing SERCA expression levels, which are known to be reduced in HF (Hobai & O'Rourke, ).…”