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

Abstract

BackgroundThe adipokine leptin and its receptor are expressed in the heart, and leptin has been shown to promote cardiomyocyte hypertrophy in vitro. Obesity is associated with hyperleptinemia and hypothalamic leptin resistance as well as an increased risk to develop cardiac hypertrophy and heart failure. 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.MethodsThe 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 (LepRdb/db) or lean WT 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 (LepRS1138) were also analyzed.ResultsObesity was associated with hyperleptinemia and elevated cardiac leptin expression in both diet-induced and genetically obese mice. Enhanced LepR and STAT3 phosphorylation levels were detected in hearts of obese WT mice, but not in those with LepR mutations. Moreover, exogenous leptin continued to induce cardiac STAT3 activation in diet-induced obese mice. 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 LepRS1138 animals. LepRS1138 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). Histological analysis of hearts revealed that the inability of leptin to activate STAT3 in LepRdb/db and LepRS1138 mice was associated with reduced cardiac angiogenesis as well as increased apoptosis and fibrosis.ConclusionsOur 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. 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.

Attenuation of microRNA‐16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy

“…Our results have suggested a role of the STAT3/c‐Myc pathway in miR‐16 down‐regulation during hypertrophy, as pharmacological inhibition of either STAT3 or c‐Myc prevented the down‐regulation of miR‐16 and subsequent hypertrophy. This conclusion has been supported by previous studies showing that STAT3 activation is involved in the development of cardiac hypertrophy . In addition, a previous study reported that the STAT3/c‐Myc pathway mediated miR‐16 suppression by progestin in mammary tumour cells , further supporting our conclusion.…”

JAK2/STAT3 Pathway Was Associated with the Protective Effects of IL-22 On Aortic Dissection with Acute Lung Injury

“…Finally, the JAK2 kinase may induce phosphorylation of Tyr705 on the STAT3 that bound with the receptor, and then the activated STAT3 would enter the nucleus in a form of a dimer to bind specifically with the DNA sequences to trigger the expression of downstream target genes such as cyclin D1 , c-myc , c-Jun , bcl , bcl-xL , and mcl-I . These genes were reported to modulate the cell cycle and inhibit the cell apoptosis, which may be participated in the protective effects of vascular endothelial barrier function [ 35 – 37 ].…”

Cardiac Dysfunction Induced by Obesity Is Not Related to β-Adrenergic System Impairment at the Receptor-Signalling Pathway

“…The literature reports that the insulin resistance induced by obesity with associated hyperinsulinaemia could promote cardiac remodelling via the growth-promoting properties of insulin or by attenuating the anti-apoptotic signalling of the phosphatidylinositol 3'-kinase (PI3K)- Akt (protein kinase B [PKB]) pathway elicited by insulin receptor activation [ 59 , 61 ]. In addition to insulin, the literature also highlights that leptin induces cardiomyocyte hypertrophy in rodents [ 62 ]. Thus, hyperleptinemia presented by Ob animals may promote the activation of Ras homolog gene family, member A (RhoA)/Rho-associated coiled-coil-forming protein kinase (ROCK) and p38 mitogen-activated protein kinase (MAPK) protein translocation to the nucleus by its receptor, resulting in cardiomyocyte hypertrophy [ 63 , 64 ].…”