Decreased p110alpha catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice.
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.
Trivedi
Premal
P
Johns Hopkins University School of Medicine, Division of Cardiology, Baltimore, Maryland 21205, USA.
Yang
Ronghua
R
Barouch
Lili A
LA
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*
D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D053148:Caspase 3