cyclic-gmp and Weight-Loss

Obesity is a worldwide pandemic. Obesity-related health and economic costs are staggering. Existing strategies to combat obesity through lifestyle improvements and medical intervention have had limited success. Pharmacotherapy, in combination with lifestyle modification, may play a vital role in reversing the disease burden. However, past and current weight-loss medications have had serious safety risks, notably cardiovascular and psychiatric events.. The authors review the strategies for designing new anti-obesity drugs by describing those currently in development. They describe their target, mechanism of action and developmental or regulatory status. Furthermore, they discuss the problem of weight regain following weight loss, and its relevance to the long-term success of anti-obesity pharmacotherapy.. For weight management drugs to achieve the safety and efficacy required to be impactful, current studies are uncovering and characterizing new targets, including new signaling circuits and hormones regulating appetite and metabolism, and re-evaluating the role of pharmacotherapy in weight management. To avoid the safety failures of many past weight-loss drugs, the models and strategies covered in this article incorporate recent advances in knowledge and technology. We discuss the emergence of cGMP signaling as a potentially transformative target in weight management. Modulating cGMP signaling may represent an ideal goal for an anti-obesity pharmacotherapy, reflecting some of the major themes described in the present review: targeting pathways that are newly realized as relevant for weight management; promoting safety by re-purposing drugs that are safe, proven, and approved for clinical use; and having a synergistic effect on multiple, reinforcing pathways.

Topics: Anti-Obesity Agents; Appetite Depressants; Cyclic GMP; Drug Design; Humans; Life Style; Models, Theoretical; Obesity; Weight Gain; Weight Loss

Central obesity shows impaired platelet responses to the antiaggregating effects of nitric oxide (NO), prostacyclin, and their effectors--guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP). The influence of weight loss on these alterations is not known. To evaluate whether a diet-induced body-weight reduction restores platelet sensitivity to the physiological antiaggregating agents and reduces platelet activation in subjects affected by central obesity, we studied 20 centrally obese subjects before and after a 6-month diet intervention aiming at reducing body weight by 10%, by measuring (i) insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA(IR))); (ii) plasma lipids; (iii) circulating markers of inflammation of adipose tissue and endothelial dysfunction, and of platelet activation (i.e., soluble CD-40 ligand (sCD-40L) and soluble P-selectin (sP-selectin)); (iv) ability of the NO donor sodium nitroprusside (SNP), the prostacyclin analog Iloprost and the cyclic nucleotide analogs 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) and 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) to reduce platelet aggregation in response to adenosine-5-diphosphate (ADP); and (v) ability of SNP and Iloprost to increase cGMP and cAMP. The 10 subjects who reached the body-weight target showed significant reductions of insulin resistance, adipose tissue, endothelial dysfunction, and platelet activation, and a significant increase of the ability of SNP, Iloprost, 8-Br-cGMP, and 8-Br-cAMP to reduce ADP-induced platelet aggregation and of the ability of SNP and Iloprost to increase cyclic nucleotide concentrations. No change was observed in the 10 subjects who did not reach the body-weight target. Changes of platelet function correlated with changes of HOMA(IR). Thus, in central obesity, diet-induced weight loss reduces platelet activation and restores the sensitivity to the physiological antiaggregating agents, with a correlation with improvements in insulin sensitivity.

Topics: Adenosine Diphosphate; Adipose Tissue; Adult; Blood Platelets; Cyclic AMP; Cyclic GMP; Diet, Reducing; Endothelium, Vascular; Epoprostenol; Female; Humans; Iloprost; Insulin Resistance; Male; Nitric Oxide; Nitroprusside; Obesity, Abdominal; Platelet Activation; Platelet Aggregation Inhibitors; Weight Loss

Effect of deficiency in endogenous arginine synthesis was studied in connection with NO synthesis and blood pressure. Rats with massive resection of small intestine were fed an arginine-free diet (AF rats) for 24 days. Control rats were pair-fed an isonitrogenous and isocaloric arginine-replete diet. AF rats lost weight by a mean of 28 g whereas control rats kept original weight. Urinary excretion of nitrate and cGMP was reduced in AF rats by about 40% after the feeding. Blood pressure became elevated by 20-25 mmHg in AF rats after the feeding. The concentrations of arginine in muscle and plasma of AF rats were reduced to 17 and 39%, respectively, of control rats. AF rats may be a novel animal model for the in vivo study of NO.

Topics: Amino Acids; Animals; Arginine; Blood Pressure; Creatinine; Cyclic GMP; Eating; Hypertension; Intestine, Small; Muscles; Nitrates; Nitric Oxide; Orotic Acid; Pulse; Rats; Rats, Sprague-Dawley; Reference Values; Weight Loss