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

Academic Article

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. © The Physiological Society 2005.
  • Authors

    Digital Object Identifier (doi)

    Author List

  • Minhas KM; Khan SA; Raju SVY; Phan AC; Gonzalez DR; Skaf MW; Lee K; Tejani AD; Saliaris AP; Barouch LA
  • Start Page

  • 463
  • End Page

  • 474
  • Volume

  • 565
  • Issue

  • 2