s-nitro-n-acetylpenicillamine and Obesity

Leptin is a regulator of body weight and affects nitric oxide (NO) production. This study was designed to determine whether the myocardial NO-cGMP signal transduction system was altered in leptin-deficient obese mice. Contractile function, guanylyl cyclase activity, and cGMP-dependent protein phosphorylation were assessed in ventricular myocytes isolated from genetically obese (B6.V-Lepob) and age-matched lean (C57BL/6J) mice. There were no differences in baseline contraction between the lean and obese groups. After stimulation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10-6 and 10-5 M) or a membrane-permeable cGMP analog 8-bromo-cGMP (8-Br-cGMP, 10(-6) and 10(-5) M), cell contractility was depressed. However, 8-Br-cGMP had significantly greater effects in obese mice than in lean controls with percent shortening reduced by 47 vs. 39% and maximal rate of shortening decreased by 46 vs. 36%. The negative effects of SNAP were similar between the two groups. Soluble guanylyl cyclase activity was not attenuated. This suggests that the activity of the cGMP-independent NO pathway may be enhanced in obesity. The phosphorylated protein profile of cGMP-dependent protein kinase showed that four proteins were more intensively phosphorylated in obese mice, which suggests an explanation for the enhanced effect of cGMP. These results indicate that the NO-cGMP signaling pathway was significantly altered in ventricular myocytes from the leptin-deficient obese mouse model.

Topics: Animals; Cyclic GMP; Heart Ventricles; Leptin; Mice; Mice, Inbred C57BL; Mice, Obese; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide; Nitric Oxide Donors; Obesity; Penicillamine

The present study tested the hypothesis that nitric oxide (NO) is involved in the leptin-induced stimulation of lipolysis. The effect of intravenous (iv) administration of leptin (10, 100 and 1000 microg/kg body weight) or vehicle on serum NO concentrations and glycerol release from white adipocytes of Wistar rats was examined. One hour after injection, the three leptin doses tested increased serum NO concentrations 15.1%, 23.4% and 60.0%, respectively (P<.001 vs. baseline). The effect of leptin on NO concentrations was significantly dose dependent on linear trend testing (P=.0001). Simple linear regression analysis showed that the lipolytic rate measured was significantly correlated with serum NO concentrations (P=.0025; r=.52). In order to gain further insight into the potential underlying mechanisms, the effect of leptin on lipolysis was studied in the setting of nitric oxide synthase (NOS) inhibition or acute ganglionic blockade. The stimulatory effect of leptin on lipolysis was significantly decreased (P<.05) under NOS inhibition. On the contrary, the leptin-induced lipolysis was unaltered in pharmacologically induced ganglionic blockade. The lack of effect on isoproterenol-, forskolin- and dibutyryl-cyclic AMP-stimulated lipolysis suggests that leptin does not interfere with the signal transduction pathway at the beta-adrenergic receptor, the adenylate cyclase and the protein kinase A levels. These findings suggest that NO is a potential regulator of leptin-induced lipolysis.

Topics: Adipose Tissue; Animals; Cells, Cultured; Chlorisondamine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ganglionic Blockers; Leptin; Lipolysis; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Obesity; Penicillamine; Rats; Rats, Wistar; Rats, Zucker