title: Decreased p110alpha catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice.
abstract: Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, db/db, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110alpha) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110alpha catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.
authors.affiliation: Johns Hopkins University School of Medicine, Division of Cardiology, Baltimore, Maryland 21205, USA.
authors.forename: Premal
authors.initials: P
authors.lastname: Trivedi
authors.forename: Ronghua
authors.initials: R
authors.lastname: Yang
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
mesh_terms: D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000201:enzymology*; D053148:Caspase 3 / Q000378:metabolism; D002384:Catalysis; D058534:Class I Phosphatidylinositol 3-Kinases; D006333:Heart Failure / Q000201:enzymology; D020738:Leptin / Q000172:deficiency*; D051379:Mice; D008820:Mice, Obese; D032342:Muscle Cells / Q000166:cytology* / Q000201:enzymology*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*
chemical_list: D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D053148:Caspase 3