Oxytocin Treatment Prevents the Cardiomyopathy Observed in Obese Diabetic Male db/db Mice.

Oxytocin (OT) is involved in the regulation of energy metabolism and in the activation of cardio-protective mechanisms. We evaluated whether chronic treatment with OT could prevent the metabolic and cardiac abnormalities associated with diabetes and obesity using the db/db mice model. Four-week-old male db/db mice and their lean non-diabetic littermates (db/+) serving as controls were treated with OT (125 ng/kg/h) or saline vehicle for a period of 12 weeks. Compared to db/+ mice, the saline-treated db/db mice developed obesity, hyperglycemia and hyperinsulinemia. These mice also exhibited a deficient cardiac OT/natriuretic system and developed systolic and diastolic dysfunction resulting from cardiomyocytes hypertrophy, fibrosis and apoptosis. These abnormalities were associated with increased ROS production, inflammation and suppressed AMP-kinase signaling pathway. The db/db mice displayed reduced serum levels of adiponectin and adipsin and elevated resistin. OT treatment increased circulating OT levels, significantly reduced serum resistin, body fat accumulation (19%: p<0.001), fasting blood glucose levels by (23%; p<0.001), and improved glucose tolerance and insulin sensitivity. OT also normalized cardiac OT receptors, ANP and BNP expressions and prevented systolic and diastolic dysfunction as well as cardiomyocytes hypertrophy, fibrosis and apoptosis. Furthermore, OT reduced cardiac oxidative stress and inflammation, and normalized the AMP-activated protein kinase signaling pathway. The complete normalization of cardiac structure and function by OT treatment in db/db mice contrasted with only partial improvement of hyperglycemia and hyperinsulinemia. These results indicate that chronic treatment with OT partially improves glucose and fat metabolism, reverses abnormal cardiac structural remodeling, preventing cardiac dysfunction in db/db mice.