Leptin repletion restores depressed β-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy

Khalid M. Minhas, Shakil A. Khan, Shubha V.Y. Raju, Alexander C. Phan, Daniel R. Gonzalez, Mike W. Skaf, Kwangho Lee, Ankit D. Tejani, Anastasies P. Saliaris, Lili A. Barouch, Christopher P. O'Donnell, Charles W. Emala, Dan E. Berkowitz, Joshua M. Hare

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44 Scopus citations

Abstract

Impaired leptin signalling in obesity is increasingly implicated in cardiovascular pathophysiology. To explore mechanisms for leptin activity in the heart, we hypothesized that physiological leptin signalling participates in maintaining cardiac β-adrenergic regulation of excitation-contraction coupling. We studied 10-week-old (before development of cardiac hypertrophy) leptin-deficient (ob/ob, n = 12) and C57Bl/6 (wild-type (WT), n = 15) mice at baseline and after recombinant leptin infusion (0.3 mg kg-1 day-1 for 28 days, n = 6 in each group). Ob/ob-isolated myocytes had attenuated sarcomere shortening and calcium transients ([Ca2+]i) versus WT (P < 0.01 for both) following stimulation of the β-receptor (with isoproterenol (isoprenaline)) or at the post-receptor level (with forskolin and dibutryl-cAMP). In addition, sarcoplasmic reticulum (SR) Ca2+ stores were depressed. Leptin replenishment in ob/ob mice restored each of these abnormalities towards normal without affecting gross (wall thickness) or microscopic (cell size) measures of cardiac architecture. Immunoblots revealed alterations of several proteins involved in excitation-contraction coupling in the ob/ob mice, including decreased abundance of Gsα-52 kDa, as well as alterations in the expression of Ca2+ cycling proteins (increased SR Ca2+-ATPase, and depressed phosphorylated phospholamban). In addition, protein kinase A (PKA) activity in ob/ob mice was depressed at baseline and correctable towards the activity found in WT with leptin repletion, a finding that could account for impaired β-adrenergic responsiveness. Taken together, these data reveal a novel link between the leptin signalling pathway and normal cardiac function and suggest a mechanism by which leptin deficiency or resistance may lead to cardiac depression.

Original languageEnglish (US)
Pages (from-to)463-474
Number of pages12
JournalJournal of Physiology
Volume565
Issue number2
DOIs
StatePublished - Jun 1 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Physiology

Cite this

Minhas, K. M., Khan, S. A., Raju, S. V. Y., Phan, A. C., Gonzalez, D. R., Skaf, M. W., Lee, K., Tejani, A. D., Saliaris, A. P., Barouch, L. A., O'Donnell, C. P., Emala, C. W., Berkowitz, D. E., & Hare, J. M. (2005). Leptin repletion restores depressed β-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy. Journal of Physiology, 565(2), 463-474. https://doi.org/10.1113/jphysiol.2005.084566