Unlike leptin, ciliary neurotrophic factor does not reverse the starvation-induced changes of serum corticosterone and hypothalamic neuropeptide levels but induces expression of hypothalamic inhibitors of leptin signaling.
Leptin mediates neuroendocrine responses to fasting and restores the starvation-induced changes of several hypothalamic neuropeptides. Ciliary neurotrophic factor (CNTF), a cytokine closely related to leptin, reduces food intake and reverses obesity, but its role in restoring the starvation-induced changes of hormones or hypothalamic neuropeptides remains largely unknown. To comparatively assess the roles of CNTF and leptin in reversing the starvation-induced changes of hypothalamic neuropeptides and endocrine function and in inducing expression of hypothalamic inhibitors of leptin and CNTF signaling (suppressor of cytokine signaling 3 [SOCS-3]) and mediators of energy expenditure (cyclo-oxygenase 2 [COX-2]), we studied the effect of CNTF and leptin administered by intraperitoneal injections (1 microg/g twice daily) in C57Bl/6J mice fasted for 48 h. Serum corticosterone levels increased with fasting, and leptin administration partially normalized them, whereas CNTF administration had no effect. Hypothalamic neuropeptide Y (NPY) and agouti-related protein (AgRP) mRNA expression increased and pro-opiomelanocortin (POMC) decreased in response to fasting. Leptin administration decreased NPY and AgRP and increased POMC mRNA levels toward baseline, but CNTF administration in fasted mice had no effect of comparable significance. Both leptin and CNTF administration in fasted mice resulted in an induction of SOCS-3 mRNA expression. CNTF also induced hypothalamic SOCS-2 mRNA expression. Finally, neither leptin nor CNTF administration in mice fasted for 48 h alters hypothalamic COX-2 expression. Our data suggest that only falling leptin levels mediate the starvation-induced alterations in corticosterone levels and expression of hypothalamic neuropeptides, but inhibitors of leptin signaling are induced by both leptin and CNTF. This may be of clinical importance because both agents are now being evaluated for the treatment of obesity in humans.
Ziotopoulou
M
M
Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Erani
D M
DM
Hileman
S M
SM
Bjørbaek
C
C
Mantzoros
C S
CS
D000199:Actins / Q000235:genetics; D054369:Agouti-Related Protein; D000818:Animals; D001835:Body Weight; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood*; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D005215:Fasting; D015870:Gene Expression / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000235:genetics; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors
D000199:Actins; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D020738:Leptin; D009478:Neuropeptide Y; D009479:Neuropeptides; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D003345:Corticosterone