Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance.
Receptor subunits for the neurocytokine ciliary neurotrophic factor (CNTF) share sequence similarity with the receptor for leptin, an adipocyte-derived cytokine involved in body weight homeostasis. We report here that CNTF and leptin activate a similar pattern of STAT factors in neuronal cells, and that mRNAs for CNTF receptor subunits, similarly to the mRNA of leptin receptor, are localized in mouse hypothalamic nuclei involved in the regulation of energy balance. Systemic administration of CNTF or leptin led to rapid induction of the tis-11 primary response gene in the arcuate nucleus, suggesting that both cytokines can signal to hypothalamic satiety centers. Consistent with this idea, CNTF treatment of ob/ob mice, which lack functional leptin, was found to reduce the adiposity, hyperphagia, and hyperinsulinemia associated with leptin deficiency. Unlike leptin, CNTF also reduced obesity-related phenotypes in db/db mice, which lack functional leptin receptor, and in mice with diet-induced obesity, which are partially resistant to the actions of leptin. The identification of a cytokine-mediated anti-obesity mechanism that acts independently of the leptin system may help to develop strategies for the treatment of obesity associated with leptin resistance.
Gloaguen
I
I
Istituto di Ricerche di Biologia Molecolare P. Angeletti (IRBM), Via Pontina km 30.600, 00040 Pomezia, Rome, Italy.
Costa
P
P
Demartis
A
A
Lazzaro
D
D
Di Marco
A
A
Graziani
R
R
Paonessa
G
G
Chen
F
F
Rosenblum
C I
CI
Van der Ploeg
L H
LH
Cortese
R
R
Ciliberto
G
G
Laufer
R
R
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism / Q000502:physiology / Q000503:physiopathology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000502:physiology / Q000503:physiopathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000502:physiology; D002460:Cell Line; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology / Q000628:therapy*; D004041:Dietary Fats; D006120:Grooming / Q000187:drug effects; D006801:Humans; D006822:Hybrid Cells; D007328:Insulin / Q000097:blood; D020738:Leptin; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009043:Motor Activity / Q000187:drug effects; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009447:Neuroblastoma; D009474:Neurons / Q000502:physiology; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D017354:Point Mutation; D011506:Proteins / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D020801:Receptor, Ciliary Neurotrophic Factor; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology
D001786:Blood Glucose; D002352:Carrier Proteins; D020934:Ciliary Neurotrophic Factor; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D007328:Insulin; C515448:LEPR protein, human; D020738:Leptin; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011506:Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D017475:Receptors, Nerve Growth Factor; D011994:Recombinant Proteins; C515447:leptin receptor, mouse