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Cited by 59Cardiovascular Function and Risk FactorsCardiac electrophysiology and arrhythmiasCardiac Fibrosis and Remodeling

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

Minhas, Khalid M., Khan, Shakil A., Raju, Shubha V. Y., Phan, Alexander C., Gonzalez, Daniel R., Skaf, Mike W., Lee, Kwangho, Tejani, Ankit D. +6 more·2005·The Journal of Physiology
DOI 10.1113/jphysiol.2005.084566
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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 ([Ca 2+]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) Ca 2+ 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 G s α‐52 kDa, as well as alterations in the expression of Ca 2+ cycling proteins (increased SR Ca 2+‐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.

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Crossref · 10.1113/jphysiol.2005.084566

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  • There is reduced β-adrenergic responsiveness in cardiomyocytes isolated from ob/ob mice.

    “In addition, others have shown that there is reduced β-adrenergic responsiveness in cardiomyocytes isolated from ob/ob mice (238).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [238]

  • Depressed cardiac response to β-adrenergic agonists is observed in ob/ob mice and can be corrected by leptin replacement therapy.

    “Another characteristic marker of heart failure, depressed cardiac response to β-adrenergic agonists, is also observed in ob/ob mice and can be corrected by leptin replacement therapy (238).”

    From Cardiac remodeling in obesity (2008) · cites this paper as [238]

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Authors
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.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2005-06
Volume
565
Issue
2
Pages
463-474
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jphysiol.2005.084566
OpenAlex
W2165961251
Cited by
59
References
52
Citations by year
2025: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 4 · 2018: 1 · 2016: 1 · 2015: 8 · 2014: 2 · 2013: 3 · 2012: 2
FWCI
4.51
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 12 d)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (KO8 HL-076220, K08HL076220, R01HL065455)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
leptin, leptin deficiency, ob/ob mice, excitation-contraction coupling, cardiac hypertrophy, sarcoplasmic reticulum calcium, calcium transients, sarcomere shortening, Gsα, sarcoplasmic reticulum Ca2+-ATPase, phospholamban, protein kinase A, obesity, heart failure
MeSH terms
Cyclic AMP, Adenylyl Cyclases, Adrenergic beta-Agonists, Age Factors, Animals, Calcium, Cardiomegaly, Isoproterenol, Mice, Inbred C57BL, Mice, Obese, Myocardial Contraction, Obesity, Phenotype, Receptors, Adrenergic, beta, Sarcoplasmic Reticulum, Blotting, Western, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, Leptin, Mice, Receptors, Leptin

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