Abstract | BACKGROUND: 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.
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Authors | Maren Leifheit-Nestler, Nana-Maria Wagner, Rajinikanth Gogiraju, Michael Didié, Stavros Konstantinides, Gerd Hasenfuss, Katrin Schäfer |
Journal | Journal of translational medicine
(J Transl Med)
Vol. 11
Pg. 170
(Jul 11 2013)
ISSN: 1479-5876 [Electronic] England |
PMID | 23841921
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Leptin
- Receptors, Leptin
- STAT3 Transcription Factor
- Stat3 protein, mouse
- Tyrosine
- Serine
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Topics |
- Animals
- Cardiomegaly
(complications, metabolism)
- Echocardiography
- Immunohistochemistry
- Leptin
(metabolism)
- Mice
- Mice, Transgenic
- Mutation
- Obesity
(complications, metabolism)
- Phenotype
- Receptors, Leptin
(metabolism)
- STAT3 Transcription Factor
(metabolism)
- Serine
(metabolism)
- Signal Transduction
- Tyrosine
(metabolism)
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