Involvement of central microsomal prostaglandin E synthase-1 in IL-1beta-induced anorexia.
In response to infection or inflammation, individuals develop a set of symptoms referred to as sickness behavior, which includes a decrease in food intake. The characterization of the molecular mechanisms underlying this hypophagia remains critical, because chronic anorexia may represent a significant health risk. Prostaglandins (PGs) constitute an important inflammatory mediator family whose levels increase in the brain during inflammatory states, and their involvement in inflammatory-induced anorexia has been proposed. The microsomal PGE synthase (mPGES)-1 enzyme is involved in the last step of PGE2 biosynthesis, and its expression is stimulated by proinflammatory agents. The present study attempted to determine whether an upregulation of mPGES-1 gene expression may account for the immune-induced anorexic behavior. We focused our study on mPGES-1 expression in the hypothalamus and dorsal vagal complex, two structures strongly activated during peripheral inflammation and involved in the regulation of food intake. We showed that mPGES-1 gene expression was robustly upregulated in these structures after intraperitoneal and intracerebroventricular injections of anorexigenic doses of IL-1beta. This increase was correlated with the onset of anorexia. The concomitant reduction in food intake and central mPGES-1 gene upregulation led us to test the feeding behavior of mice lacking mPGES-1 during inflammation. Interestingly, IL-1beta failed to decrease food intake in mPGES-1(-/-) mice, although these animals developed anorexia in response to a PGE2 injection. Taken together, our results demonstrate that mPGES-1, which is strongly upregulated during inflammation in central structures involved in feeding control, is essential for immune anorexic behavior and thus may constitute a potential therapeutic target.
Laboratoire de Physiologie Neurovégétative, UMR 6153 Centre National de la Recherche Scientifique-1147 Institut National de la Recherche Agronomique, Université Paul Cézanne, Marseille, France.
E
E
Pecchi
M
M
Dallaporta
S
S
Thirion
C
C
Salvat
F
F
Berenbaum
A
A
Jean
J-D
JD
Troadec
D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000201:enzymology*; D001835:Body Weight / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000633:toxicity; D004435:Eating / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000633:toxicity*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation; D014630:Vagus Nerve / Q000187:drug effects / Q000201:enzymology
D053583:Interleukin-1beta; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone