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.