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Ciliary NeuroTrophic Factor (CNTF)


Neurogenesis in the Hypothalamus of Adult Mice: Potential Role in Energy Balance.
Ciliary neurotrophic factor (CNTF) induces weight loss in obese rodents and humans, and for reasons that are not understood, its effects persist after the cessation of treatment. Here we demonstrate that centrally administered CNTF induces cell proliferation in feeding centers of the murine hypothalamus. Many of the newborn cells express neuronal markers and show functional phenotypes relevant for energy-balance control, including a capacity for leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Coadministration of the mitotic blocker cytosine--D-arabinofuranoside (Ara-C) eliminates the proliferation of neural cells and abrogates the long-term, but not the short-term, effect of CNTF on body weight. These findings link the sustained effect of CNTF on energy balance to hypothalamic neurogenesis and suggest that regulated hypothalamic neurogenesis in adult mice may play a previously unappreciated role in physiology and disease.
Maia V. Kokoeva, Huali Yin, Jeffrey S. Flier. Science 28 October 2005: Vol. 310. no. 5748, pp. 679 - 683, DOI: 10.1126/science.1115360
The Regulation and Activation of Ciliary Neurotrophic Factor Signaling Proteins in Adipocytes
Zvonic S. et al. J. Biol. Chem., Vol. 278, Issue 4, 2228-2235, January 24, 2003

CNTF triggers weight loss and neurogenesis.
Leptin provides a key feedback signal from peripheral adipose to two types of neurons in the arcuate nucleus of the hypothalamus. POMC neurons (brown) are activated by leptin and inhibit food intake and increase energy expenditure, whereas AgRP/NPY neurons (blue) have the opposite response to leptin and the opposite effect on energy balance. Before CNTF is administered, body fat has expanded because the key central nervous system targets of leptin are less responsive. During CNTF treatment, body weight is lowered because CNTF mimics leptin effects in the hypothalamus. In addition, CNTF treatment stimulates the formation of new neurons (orange) involved in weight regulation, as shown by Kokoeva et al. After CNTF treatment, these new neurons increase the effects of leptin and thereby keep adipose mass from returning to its previous levels. Randy J Seeley. Nature Medicine 11, 1276 - 1278 (2005)
CNTF
CNTF
CNTF reduces body weights long term and induces cell proliferation in the hypothalamus. (A) Mice were icv infused for 7 days with BrdU (12 g/day) in artificial cerebrospinal fluid alone or together with CNTF (0.75 g/day) at a flow rate of 12 l/day. Body weight (BW) is shown as percentage difference from initial body weight. All data are mean SEM (n = 5 animals per group). (B) BrdU-labeled cells in coronal sections of the hypothalamus on the level of the arcuate nucleus. (C) In situ hybridization with a digoxygenin-labeled probe directed against CNTFR mRNA. Blue precipitate indicates staining. (D) Fluorescence image of the same section reveals BrdU+ cells (red). (Insets) High-power magnification of BrdU+ cells that express CNTFR (arrowheads). (E) Total number of BrdU+ cells detected in the caudal hypothalamus of vehicle- and CNTF-infused animals. Brains were inspected at the indicated times after surgery. Error bars represent mean SEM (n = 3 animals per group). 3V, third ventricle; Arc, arcuate nucleus; Me, median eminence. Scale bars, 100 m. Maia V. Kokoeva, Huali Yin, Jeffrey S. Flier. Science 28 October 2005: Vol. 310. no. 5748, pp. 679 - 683, DOI: 10.1126/science.1115360
CNTF
Newborn hypothalamic cells respond to leptin. Many BrdU+ (red) cells of CNTF-treated mice were also positive for pSTAT3 (green) after ip leptin injection. (B) 3D confocal reconstruction of area boxed in (A). (C) Groups of DIO or ob/ob mice (n = 5) were icv infused for 7 days with CNTF (0.75 g/day) or leptin (0.60 g/day). For all animals, BrdU (12 g/day) was coadministered. To induce DIO, mice were placed on a high-fat diet for 5 months. Body weight is shown as percentage difference from initial body weight. All data are mean SEM. Scale bars in (A), 50 m; in (B), 10 m. Maia V. Kokoeva, Huali Yin, Jeffrey S. Flier. Science 28 October 2005: Vol. 310. no. 5748, pp. 679 - 683, DOI: 10.1126/science.1115360
In situ hybridization combined with anti-BrdU immunohistochemistry reveals newborn cells expressing NPY and POMC. Coronal sections at the level of the arcuate nucleus of a CNTF-treated mouse 42 days after surgery. (A) Brain section after hybridization to a digoxigenin-labeled probe for POMC. Inset left: High-power magnification of a POMC expressing cell (arrow). Inset right: Fluorescence image of the same cell demonstrating colocalization with BrdU. (B) Brain section hybridized to a NPY probe. The NPY-expressing cell marked by an arrow is also positive for BrdU (Insets). Scale bars: 100 m. Maia V. Kokoeva, Huali Yin, Jeffrey S. Flier. Science 28 October 2005: Vol. 310. no. 5748, pp. 679 - 683, DOI: 10.1126/science.1115360
CNTF
Schematic representation of hypothalamic signaling pathways in the regulation of appetite and energy expenditure. NPY, AgrP, and GABA, the appetite-stimulating signals, are coproduced in the perikarya located in the ARC. Likewise, the appetite-inhibiting peptides, -MSH and CART, are coproduced in the POMC/CART coexpressing perikarya in the ARC. These distinct populations of neurons project into the two subdivisions of the PVN, the mPVN and pPVN, to activate their corresponding receptors for regulation of appetite and energy expenditure. NPY-producing neurons also contact the POMC/CART neurons locally in the ARC to curtail their tonic restraint on appetite. Leptin inhibits appetite through leptin-Rb located on the NPY/AgrP/GABA- and POMC/CART-expressing cell bodies in the ARC and at postsynaptic sites in the PVN where it regulates release of these signals and enhances energy expenditure through the sympathetic nervous system. The results show that CNTF/CNTFAx15, through activation of the CNTFR located in the ARC and PVN, markedly diminish the availability of NPY for release in the PVN by suppressing its synthesis in the ARC and concurrently attenuating postsynaptic NPYergic signaling by decreasing NPY Y1 receptor and pCREB abundance. Kalra SP. Circumventing leptin resistance for weight control. Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4279-81
CNTF
DR reverses abnormal phenotypes of BDNF+/- mice. Wild-type (WT) and BDNF+/- mice were maintained for 3 months on AL or DR feeding regimens. A, Body weights: *, P < 0.05 compared with the WT-AL value; **, P < 0.01 compared with the corresponding value for AL-fed mice. B, Food intake: *, P < 0.05 compared with the WT-AL value; **, P < 0.01 compared with the BDNF+/- AL value. C, Spontaneous activity: *, P < 0.05 compared with the WT-AL value; **, P < 0.01 compared with the BDNF+/- AL value. D, BDNF concentration: *, P < 0.01 compared with the corresponding value for mice fed AL. All values are the mean and SEM of determinations made in 8–10 mice per group; statistical comparisons were made using ANOVA and Scheff’s post hoc tests. Duan W., et al. Endocrinology Vol. 144, No. 6 2446-2453
CNTF
Hyperglycemia and impaired glucose tolerance in BDNF+/- mice are normalized by DR. Wild-type (WT) and BDNF+/- mice were maintained for 3 months on AL or DR feeding regimens. A and B, Glucose concentrations were measured in blood samples taken after an overnight fast (A) or during feeding conditions (B). Note that the scales for the glucose concentrations in the two graphs are different. *, P < 0.01 compared with the value for the same genotype of mice fed AL; #, P < 0.05 cmpared to the WT-AL value. C, Mice were administered an oral bolus of glucose (2 g/kg) and the glucose concentration in blood samples taken at the indicated times was determined. *, P < 0.01 compared with the value for each of the other three groups at that time point. Values are the mean and SEM of measurements made in 8–10 mice per group. Statistical comparisons were made using ANOVA and Scheff’s post hoc tests. Duan W., et al. Endocrinology Vol. 144, No. 6 2446-2453
CNTF
Mice with reduced BDNF levels exhibit insulin insensitivity that is normalized by DR. Wild-type (WT) and BDNF+/- mice were maintained for 3 months on AL or DR feeding regimens. A and B, Insulin concentrations were measured in blood samples taken after an overnight fast (A) or during feeding conditions (B). *, P < 0.001 compared with the value for the same genotype of mice fed AL; **, P < 0.001 compared with the WT-AL value. C, Mice were administered insulin (1 U/kg) and the glucose concentration in blood samples taken at the indicated times was determined. *, P < 0.01 compared with the value for each of the other three groups at that time point. Values are the mean and SEM of measurements made in 8–10 mice per group. Statistical comparisons were made using ANOVA and Scheff’s post hoc tests. Duan W., et al. Endocrinology Vol. 144, No. 6 2446-2453
CNTF
gp130 cytokine family pathways on anterior pituitary cells. Following immune (e.g., LPS) or hormonal (e.g., PACAP) stimulation, systemic or anterior pituitary gp130 cytokines, expressed by FS cells among others, induce the stimulation of ACTH (detailed in the scheme) in the pituitary. In this pathway, which is distinct from another mechanism activated by CRH or IL-1, POMC expression and ACTH secretion are stimulated through STAT3, providing a new powerful mechanism for regulation of corticotroph function. Arzt E. J Clin Invest, December 2001, Volume 108, Number 12, 1729-1733
Schematic model of the IL-6/gp130 receptor system. The specific cytokine-binding subunits and gp130 belong to a cytokine receptor superfamily characterized by four positionally conserved cysteine residues and a WSXWS motif. Functional receptor complexes are induced by the different gp130 cytokines: IL-6 and IL-11 induce gp130 homodimerization; CNTF, LIF, CT-1, and OSM induce LIFR/gp130 heterodimers; and OSM may also induce OSMR/gp130 heterodimers. Following ligand binding, gp130 is responsible for signal transduction through the JAK/STAT pathways.
CNTF
CNTF does not cause insulin resistance but increases GLUT 4 expression. A, whole cell extracts were prepared from fully differentiated 3T3-L1 adipocytes treated with 0.8 nM CNTF for the times shown. Seventy-five g of each extract was separated by SDS-PAGE, transferred to nitrocellulose, and subjected to Western blot analysis. Samples were processed, and results were visualized as described in Fig. 1 legend. B, fully differentiated 3T3-L1 adipocytes were treated with CNTF for 72 h. A fresh bolus of CNTF was added to the cells every 24 h. Monolayers of adipocytes were used to examine glucose uptake as indicated under "Experimental Procedures." This is a representative experiment independently performed four times. Zvonic S., et al. J. Biol. Chem., Vol. 278, Issue 4, 2228-2235, January 24, 2003
CNTF
Time- and dose-dependent effects of CNTF administration on the phosphorylation and nuclear translocation of STAT proteins in 3T3-L1 cells. A, cytosolic and nuclear extracts were prepared from fully differentiated 3T3-L1 adipocytes following a treatment with 0.8 nM CNTF for the times indicated at the top of the figure. B, cytosolic and nuclear extracts were prepared from fully differentiated 3T3-L1 adipocytes following a 10-min treatment with CNTF at the doses indicated. C, whole cell extracts were prepared from both preadipocytes and from fully differentiated 3T3-L1 adipocytes following a 10-min treatment with CNTF at the doses shown in the figure. Seventy- five g of each extract was separated by SDS-PAGE, transferred to nitrocellulose, and subjected to Western blot analysis. Samples were processed, and the results were visualized as described in Fig. 1 legend. This is a representative experiment independently performed three times. Zvonic S., et al. J. Biol. Chem., Vol. 278, Issue 4, 2228-2235, January 24, 2003
CNTF
The effects of acute CNTF administration on the expression of adipocyte proteins. Whole cell extracts were prepared from fully differentiated 3T3-L1 adipocytes treated with 0.8 nM CNTF for the times shown. Seventy-five g of each extract was separated by SDS-PAGE, transferred to nitrocellulose, and subjected to Western blot analysis. Samples were processed and results were visualized as described in Fig. 1 legend. This is a representative experiment independently performed three times.
Zvonic S., et al. J. Biol. Chem., Vol. 278, Issue 4, 2228-2235, January 24, 2003
CNTF
The effects of chronic CNTF administration on the expression of adipocyte proteins. Whole cell extracts were prepared from fully differentiated 3T3-L1 adipocytes treated with 0.8 nM CNTF for the times indicated at the top of the figure. Seventy-five g of each extract was separated by SDS-PAGE, transferred to nitrocellulose, and subjected to Western blot analysis. Samples were processed, and results were visualized as described in Fig. 1 legend. This is a representative experiment independently performed three times. Zvonic S., et al. J. Biol. Chem., Vol. 278, Issue 4, 2228-2235, January 24, 2003
CNTF
In vivo effect of acute CNTF administration in rodents. Six-week-old C57Bl/6J mice were given an intraperitoneal injection of CNTF (33.3 g/kg) or vehicle (saline) control. Fifteen minutes after the injection, the mice were sacrificed, and epididymal fat pads, brains, and skeletal muscle were immediately removed and frozen in liquid nitrogen. Tissue extracts were analyzed from epididymal fat pads (A) and brain and skeletal muscle (B). In each panel, 75 g of each extract was separated by SDS-PAGE, transferred to nitrocellulose, and subjected to Western blot analysis. Samples were processed, and results were visualized as described in Fig. 1 legend. This is a representative experiment independently performed two times. Zvonic S., et al. J. Biol. Chem., Vol. 278, Issue 4, 2228-2235, January 24, 2003
CNTF

In vivo expression of CNTFR in epididymal fat pads. Epididymal fat pads were extracted from 6-week-old lean C57Bl/6J mice and fractionated into adipocyte and stromovascular fractions. Seventy-five g of each extract was separated by SDS-PAGE, transferred to nitrocellulose, and subjected to Western blot analysis. Samples were processed, and results were visualized as described in Fig. 1 legend. Zvonic S., et al. J. Biol. Chem., Vol. 278, Issue 4, 2228-2235, January 24, 2003

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