Analysis of cardiomyocytes ex vivo revealed that leptin promotes hypertrophy via activation of p38 and p42/44 MAP kinases as well as protein kinase B (Akt). The leptin receptor (LepR) belongs to the family of cytokine type I receptors known to signal via activation of Janus kinase (Jak)-2 and signal transducer and activator of transcription (STAT)-3. Thus, the role of the adipokine in mediating cardiac hypertrophy, in particular in the presence of elevated systemic leptin levels, and the possible existence of a cardiac leptin resistance in obesity remains unclear. While the effects of leptin on cell shortening and intracellular Ca 2+ transients were found to be abrogated in cardiomyocytes isolated from HFD-fed obese rats, others reported a preserved signal transduction in response to leptin in hyperleptinemic obese mice or rats. Ĭardiac hypertrophy also develops in obese rodents fed high-fat diet (HFD), and studies in mice with (functional) leptin deficiency suggested that the cardiac hypertrophy developing in states of chronic hyperleptinemia may result from the inability to transduce anti-hypertrophic and/or cardioprotective effects of the adipokine. Furthermore, leptin was shown to promote hypertrophy of isolated rat or human ventricular cardiomyocytes, and this effect could be prevented using neutralizing antibodies. Clinical studies demonstrated a positive correlation between serum leptin levels and left ventricular (LV) mass or wall thickness, independent of blood pressure levels, suggesting a direct role for leptin in the pathogenesis of obesity-associated cardiomyopathy. Obesity is frequently associated with elevated circulating leptin levels and an increased risk to develop cardiac hypertrophy or heart failure. On the other hand, the presence of cardiac hypertrophy in obese mice with complete LepR signal disruption indicates that additional pathways also play a role. Our findings suggest that hearts from obese mice continue to respond to elevated circulating or cardiac leptin, which may mediate cardioprotection via LepR-induced STAT3 activation, whereas signals distinct from LepR-Tyr1138 promote cardiac hypertrophy. Histological analysis of hearts revealed that the inability of leptin to activate STAT3 in LepR db/db and LepR S1138 mice was associated with reduced cardiac angiogenesis as well as increased apoptosis and fibrosis. LepR S1138 mice also exhibited an increased activation of signaling proteins downstream of LepR, including Jak2 (1.8-fold), Src kinase (1.7-fold), protein kinase B (1.3-fold) or C (1.6-fold). Although echocardiography revealed signs of cardiac hypertrophy in all obese mice, the increase in left ventricular (LV) mass and diameter was significantly more pronounced in LepR S1138 animals. Moreover, exogenous leptin continued to induce cardiac STAT3 activation in diet-induced obese mice. Enhanced LepR and STAT3 phosphorylation levels were detected in hearts of obese WT mice, but not in those with LepR mutations. ![]() Obesity was associated with hyperleptinemia and elevated cardiac leptin expression in both diet-induced and genetically obese mice. To study the role of leptin-mediated STAT3 activation during obesity-induced cardiac remodeling, mice in which tyrosine residue 1138 within LepR had been replaced with a serine (LepR S1138) were also analyzed. The cardiac phenotype of high-fat diet (HFD)-induced obese wildtype (WT) mice was examined and compared to age-matched genetically obese leptin receptor (LepR)-deficient (LepR db/db) or lean WT mice. However, the role of cardiac leptin signaling in mediating the cardiomyopathy associated with increased body weight is unclear, in particular, whether it develops subsequently to cardiac leptin resistance or overactivation of hypertrophic signaling pathways via elevated leptin levels. Obesity is associated with hyperleptinemia and hypothalamic leptin resistance as well as an increased risk to develop cardiac hypertrophy and heart failure. The adipokine leptin and its receptor are expressed in the heart, and leptin has been shown to promote cardiomyocyte hypertrophy in vitro.
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