The effect of prolonged metformin treatment on the activity of the adenylyl cyclase system and NO-synthase in the brain and myocardium of obese rats

Abstract

The biguanide metformin, which is widely used for the treatment of type 2 diabetes, improves carbohydrate and lipid metabolism and has substantial cardioand neuroprotective effects. The positive effects of metformin on the activity of NO synthases catalyzing the synthesis of NO, a major vasodilator, and that of the hormone-sensitive adenylyl cyclase signaling system (ACSS) are believed to play an important role in the mediation of these effects. To prove this hypothesis, we initiated a study addressing the effect of prolonged metformin treatment of obese rats on metabolic parameters and the activity of ACSS and NO synthases in the myocardium and brain of the animals. Obesity was induced in Wistar rats by a high-fat diet, and the animals were subsequently treated with metformin for 2 months (the daily dose was 200 mg/kg). Metformin treatment induced a decrease in adipose tissue mass, total body mass, levels of insulin and glucose, and the insulin resistance index HOMA-IR, as well as improved glucose tolerance, and led to a decrease of the content of atherogenic forms of cholesterol. ACSS stimulation by agonists of β1/β2-adrenergic receptors (ARs) and enhancement of β3-AR signaling was detected in the myocardium of obese rats, while metformin treatment restored ACSS regulation by adrenergic agonists in the myocardium and normalized the balance between β-AR-signaling pathways. The stimulating effects of serotonin and agonists of type 4 melanocortin receptors on adenylyl cyclase, which are attenuated in obesity, were restored in the brain of rats treated with metformin. The treatment completely restored the total activity of NO synthases and the activity of endothelial NO synthase in the myocardium, which are reduced in obesity. Metformin treatment was also shown to induce hyperactivation of NO synthases in the brain and myocardium of healthy animals. It is proposed the effects of prolonged treatment of obese rats with metformin underlie the cardioand neuroprotective actions of this drug.