title: Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy.
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 beta-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 beta-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 Gsalpha-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 beta-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.
authors.affiliation: The Johns Hopkins Medical Institutions, Cardiology Division, 720 Rutland Avenue, Ross 1059, Baltimore, MD 21205, USA.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Minhas
authors.forename: Shakil A
authors.initials: SA
authors.lastname: Khan
authors.forename: Shubha V Y
authors.initials: SV
authors.lastname: Raju
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Phan
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Gonzalez
authors.forename: Mike W
authors.initials: MW
authors.lastname: Skaf
authors.forename: Kwangho
authors.initials: K
authors.lastname: Lee
authors.forename: Ankit D
authors.initials: AD
authors.lastname: Tejani
authors.forename: Anastasios P
authors.initials: AP
authors.lastname: Saliaris
authors.forename: Anastasies P
authors.initials: AP
authors.lastname: Saliaris
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Hare
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D020738:Leptin / Q000097:blood / Q000235:genetics* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010641:Phenotype; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D054411:Receptors, Leptin; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D020738:Leptin; D011943:Receptors, Adrenergic, beta; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002118:Calcium