cyclic-gmp and Anorexia

Lipopolysaccharide (LPS) induces anorexia and expression of inducible nitric oxide synthase (iNOS) in the hypothalamic arcuate nucleus (Arc). Peripheral administration of the iNOS inhibitor 1400 W counteracts the anorectic effects of LPS. Here we investigated the role of central NO signaling in LPS anorexia. In electrophysiological studies we tested whether 1400 W counteracts the iNOS-dependent inhibition of Arc neurons triggered by in vivo or in vitro stimulation with LPS. We used the hormone ghrelin as a functional reference stimulus because ghrelin is known to activate orexigenic Arc neurons. Further, we investigated whether in vitro LPS stimulation induces an iNOS-mediated formation of the second messenger cGMP. Since the STAT1 pathway contributes to the regulation of iNOS expression we investigated whether LPS treatment induces STAT1 phosphorylation in the Arc. Finally we tested the effect of intracerebroventricular injection of 1400 W on LPS-induced anorexia. Superfusion with 1400 W (10(-4) M) increased neuronal activity in 37% of neurons in Arc slices from LPS treated (100 μg/kg ip) but not from saline treated rats. Similarly, 1400 W excited 45% of Arc neurons after in vitro stimulation with LPS (100 ng/ml). In both approaches, a considerable percentage of 1400 W sensitive neurons were excited by ghrelin (10(-8)M; 50% and 75%, respectively). In vitro stimulation with LPS induced cGMP formation in the Arc, which was blocked by co-incubation with 1400 W. LPS treatment elicited a pSTAT1 response in the Arc of mice. Central 1400 W injection (4 μg/rat) attenuated LPS-induced anorexia and counteracted the LPS-dependent decrease in respiratory quotient and energy expenditure. In conclusion, the current findings substantiate a role of central iNOS dependent NO formation in LPS-induced effects on eating and energy homeostasis. A pharmacological blockade of NO formation might be a therapeutic approach to ameliorate disease-related anorexia.

Topics: Amidines; Animals; Anorexia; Arcuate Nucleus of Hypothalamus; Benzylamines; Cyclic GMP; Eating; Electrophysiological Phenomena; Enzyme Inhibitors; Ghrelin; Immunohistochemistry; Injections, Intraventricular; Lipopolysaccharides; Male; Neurons; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; Rats; Rats, Wistar; Signal Transduction; STAT1 Transcription Factor

Anorexia nervosa (AN) is associated with high cardiovascular mortality. Nitric oxide (NO) inhibits platelet function and regulates the cardiovascular homeostasis. The aim of this study was to investigate the l-arginine-NO-GMPc and arginase pathways and oxidative stress in platelets from patients with AN. Intraplatelet l-arginine transport, NOS expression and activity, cGMP levels, platelet aggregation, arginase expression and oxidative stress were measured in adolescent patients with AN (n=11) and healthy controls (n=12). Plasma l-arginine levels were significantly reduced in AN. l-arginine transport, NOS activity and cGMP basal levels were reduced in platelets associated with unchanged platelet aggregability. The expression of NOS isoforms was not affected. TBARS production was diminished, while the activity of superoxide dismutase was elevated in AN patients. There was an overexpression of arginase II in AN. Alterations of l-arginine-NO-GMPc and arginase pathways in platelets can be early predictors of the incidence of cardiovascular disease into adult life in AN.

Topics: Adolescent; Anorexia; Arginase; Arginine; Blood Platelets; Cyclic GMP; Female; Humans; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Platelet Aggregation; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances