Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity

Shubha V.Y. Raju, Meizi Zheng, Karl H. Schuleri, Alexander C. Phan, Djahida Bedja, Roberto M. Saraiva, Omer Yiginer, Koenraad Vandegaer, Kathleen L. Gabrielson, Christopher P. O'Donnell, Dan E. Berkowitz, Lili A. Barouch, Joshua M. Hare

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Disruption of the leptin signaling pathway within the heart causes left ventricular hypertrophy (LVH). Because human obesity is a syndrome of leptin resistance, which is not amenable to leptin treatment, the identification of parallel signal transduction pathways is of potential therapeutic value. Ciliary neurotrophic factor (CNTF), which acts parallel to leptin in the hypothalamus, is not previously recognized to have cardiac activity. We hypothesized that CNTF receptors are present on cardiomyocytes and their activation reverses LVH in both leptin-deficient ob/ob and leptin-resistant db/db mice. The localization of CNTF receptors (CNTFRα) to the sarcolemma in C57BL/6, ob/ob and db/db was confirmed in situ with immunohistochemistry, and immunoblotting (60 and 40 kDa) on isolated myocytes. ob/ob mice were randomly assigned to receive s.c. recombinant CNTF (CNTFAx15; 0.1 mg·kg-1 per day; n = 11) calorie-restriction (n = 9), or feeding ad libitum (n = 11). db/db mice were allocated to three similar groups (n = 8, 7, and 8, respectively) plus a leptin group (1 mg·kg-1 per day; n = 7). Echocardiography showed that CNTFAx15 reduced cardiac hypertrophy [posterior wall thickness decreased by 29 ± 8% (P < 0.01) in ob/ob and by 21 ± 3% in db/db mice (P < 0.01)], which was consistent with the reduction of myocyte width. Western blotting showed that leptin and CNTFAx15 activated Stat3 and ERK1/2 pathway in cultured adult mice cardiomyocytes and cardiac tissue from in ob/ob and db/db mice. Together, these findings support the role of a previously undescribed signaling pathway in obesity-associated cardiac hypertrophy and have therapeutic implications for patients with obesity-related cardiovascular disease and other causes of LVM.

Original languageEnglish (US)
Pages (from-to)4222-4227
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number11
DOIs
StatePublished - Mar 14 2006

Keywords

  • Axokine
  • Cardiac remodeling
  • Heart
  • Mouse
  • Signal transduction

ASJC Scopus subject areas

  • Genetics
  • General

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    Raju, S. V. Y., Zheng, M., Schuleri, K. H., Phan, A. C., Bedja, D., Saraiva, R. M., Yiginer, O., Vandegaer, K., Gabrielson, K. L., O'Donnell, C. P., Berkowitz, D. E., Barouch, L. A., & Hare, J. M. (2006). Activation of the cardiac ciliary neurotrophic factor receptor reverses left ventricular hypertrophy in leptin-deficient and leptin-resistant obesity. Proceedings of the National Academy of Sciences of the United States of America, 103(11), 4222-4227. https://doi.org/10.1073/pnas.0510460103