Lipopolysaccharide inhibits ghrelin-excited neurons and reduces food intake via central nitric oxide signaling

“Lipopolysaccharide hemmen Ghrelin-sensitive Neurone und reduzieren die Nahrungsaufnahme durch eine zentrale, Stickstoffmonoxid vermittelte Wirkung” Die Behandlung mit Lipopolysacchariden (LPS) ist eine anerkannte Methode zur Induzierung krankheitsbegleitender Anorexie. An der Entwicklung der LPS-Anorexie ist Stickstoffmonoxid (NO) beteiligt. LPS bewirkt die Expression der induzierbaren NO-Synthase (iNOS) im hypothalamischen Nucleus arcuatus (Arc), wo NO Ghrelin- aktivierte Neurone hemmt. Wie vorherige Studien zeigen, wirkt eine systemische Verabreichung des spezifischen iNOS-Inhibitors 1400W dem anorektischen LPS- Effekt entgegen. Diese Arbeit untersucht mittels intrazerebroventrikulärer 1400W- Infusion den Beitrag zentral exprimierter iNOS zur Entstehung der LPS-Anorexie. Zudem wurde immunohistochemisch getestet, ob die Phosphorylierung des Transkriptions-Faktors STAT1, welcher zur iNOS-Genexpression beiträgt, durch LPS verstärkt wird. Zentrale 1400W-Applikation schwächt den LPS-Effekt auf Futteraufnahme, Energieumsatz und respiratorischen Quotienten signifikant ab. Elektrophysiologische Untersuchungen bestätigen, dass 1400W die LPS-bedingte Hemmung orexigener Arc-Neurone aufhebt. Periphere LPS-Administration ruft eine gesteigerte STAT1-Phosphorylierung im Arc hervor. Zentrale iNOS-Exprimierung scheint somit zur Entwicklung der LPS-Anorexie beizutragen, wahrscheinlich indem NO orexigene Arc-Neurone hemmt. Daher könnte pharmakologische iNOS- Hemmung eine Therapieoption sein. “Lipopolysaccharide inhibits ghrelin-excited neurons and reduces food intake via central nitric oxide signaling” Treatment with lipopolysaccharides (LPS) is a model of inflammatory disease-related anorexia. The neuromodulator nitric oxide (NO) mediates LPS anorexia as demonstrated by peripheral administration of 1400W, which specifically inhibits inducible NO synthase (iNOS). LPS induces iNOS expression in the hypothalamic arcuate nucleus (Arc), where NO inhibits orexigenic (ghrelin-excited) neurons. This study evaluates the hypothesis that central iNOS signaling mediates LPS anorexia. The effect of third intracerebroventricular (icv) injection of 1400W on LPS-induced anorexia was investigated. Furthermore, it was tested immunohistochemically whether LPS triggers the phosphorylation of the transcription factor STAT1, which contributes to iNOS gene expression. Central 1400W infusion reversed LPS anorexia and it attenuated LPS-dependent decreases in energy expenditure and respiratory quotient. Peripheral LPS treatment induced a significant pSTAT1 response in the Arc. In independent electrophysiological studies pharmacological iNOS blockade disinhibited orexigenic Arc neurons after in vivo or in vitro treatment with LPS. In conclusion, central NO signaling seems to contribute to LPS anorexia, possibly by inhibiting ghrelin-excited neurons via iNOS-dependent NO formation. Hence, pharmacological iNOS inhibition might be a therapeutic approach to treat disease related anorexia

Lipopolysaccharide inhibits ghrelin-excited neurons of the arcuate nucleus and reduces food intake via central nitric oxide signaling

Lipopolysaccharide (LPS) induces anorexia and expression of inducible nitric oxide synthase (iNOS) in the hypothalamic arcuate nucleus (Arc). Peripheral administration of the iNOS inhibitor 1400W counteracts the anorectic effects of LPS. Here we investigated the role of central NO signaling in LPS anorexia. In electrophysiological studies we tested whether 1400W 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 1400W on LPS-induced anorexia. Superfusion with 1400W (10(-4)M) increased neuronal activity in 37% of neurons in Arc slices from LPS treated (100μg/kg ip) but not from saline treated rats. Similarly, 1400W excited 45% of Arc neurons after in vitro stimulation with LPS (100ng/ml). In both approaches, a considerable percentage of 1400W 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 1400W. LPS treatment elicited a pSTAT1 response in the Arc of mice. Central 1400W injection (4μg/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