Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain.
Ciliary neurotrophic factor (CNTF) and leptin decrease food intake and body weight. Lipopolysaccharide (LPS) is a potent exogenous pyrogen and produces anorexia via cytokine production. CNTF-, leptin-, and LPS-induced cytokines all act on type I cytokine receptors. However, it is not known if these cytokines engage similar central nervous system (CNS) pathways to exert their effects. To assess mechanisms by which these cytokines act, we examined the patterns of immediate early gene expression (SOCS-3, c-fos, and tis-11) in the brain following intravenous administration. CNTF and LPS induced gene expression in circumventricular organs; ependymal cells of the ventricles, meninges, and choroid plexus; and the arcuate nucleus of the hypothalamus. CNTF administration also induced fever and cyclooxygenase-2 mRNA expression. In contrast, we found no evidence of leptin-induced inflammation. CNTF and leptin are being assessed as potential therapeutic anti-obesity agents, and both potently reduce food intake. Our findings support the hypothesis that CNTF and leptin engage distinct CNS sites and CNTF possesses inflammatory properties distinct from leptin.
Kelly
Joseph F
JF
Department of Medicine and Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Elias
Carol F
CF
Lee
Charlotte E
CE
Ahima
Rexford S
RS
Seeley
Randy J
RJ
Bjørbaek
Christian
C
Oka
Takakazu
T
Saper
Clifford B
CB
Flier
Jeffrey S
JS
Elmquist
Joel K
JK
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D020934:Ciliary Neurotrophic Factor / Q000008:administration & dosage / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D007700:Kinetics; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D051816:Tristetraprolin; D016335:Zinc Fingers / Q000235:genetics
D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007527:Isoenzymes; D020738:Leptin; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D051816:Tristetraprolin; C497552:ZFP36 protein, human; C497554:Zfp36 protein, rat; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D018021:Lithium Chloride