title: Importance of leptin signaling and signal transducer and activator of transcription-3 activation in mediating the cardiac hypertrophy associated with obesity.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  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 (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.
  
  
  RESULTS
  Obesity 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.
  
  
  CONCLUSIONS
  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. 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.
authors.affiliation: Department of Cardiology and Pulmonary Medicine, Heart Research Center, Georg August University Medicine Goettingen, Robert Koch Strasse 40, D-37075, Göttingen, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Leifheit-Nestler
authors.forename: Nana-Maria
authors.initials: NM
authors.lastname: Wagner
authors.forename: Rajinikanth
authors.initials: R
authors.lastname: Gogiraju
authors.forename: Michael
authors.initials: M
authors.lastname: Didié
authors.forename: Stavros
authors.initials: S
authors.lastname: Konstantinides
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Katrin
authors.initials: K
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000150:complications / Q000378:metabolism*; D004452:Echocardiography; D007150:Immunohistochemistry; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010641:Phenotype; D054411:Receptors, Leptin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014443:Tyrosine; D012694:Serine