Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus
In humans and experimental animals, the administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight. To gain further insights into the mechanism(s) underlying its satiety effect, we: (i) evaluated the CNTF-dependent activation of the Janus kinase 2 (JAK2) and signal tran...
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2020.00140/full |
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| author | Wiebe Venema Ilenia Severi Jessica Perugini Eleonora Di Mercurio Marco Mainardi Margherita Maffei Saverio Cinti Saverio Cinti Antonio Giordano |
| author_facet | Wiebe Venema Ilenia Severi Jessica Perugini Eleonora Di Mercurio Marco Mainardi Margherita Maffei Saverio Cinti Saverio Cinti Antonio Giordano |
| author_sort | Wiebe Venema |
| collection | DOAJ |
| description | In humans and experimental animals, the administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight. To gain further insights into the mechanism(s) underlying its satiety effect, we: (i) evaluated the CNTF-dependent activation of the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway in mouse models where neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons can be identified by green fluorescent protein (GFP); and (ii) assessed whether CNTF promotes leptin signaling in hypothalamic feeding centers. Immunohistochemical experiments enabled us to establish that intraperitoneal injection of mouse recombinant CNTF activated the JAK2-STAT3 pathway in a substantial proportion of arcuate nucleus (ARC) NPY neurons (18.68% ± 0.60 in 24-h fasted mice and 25.50% ± 1.17 in fed mice) but exerted a limited effect on POMC neurons (4.15% ± 0.33 in 24-h fasted mice and 2.84% ± 0.45 in fed mice). CNTF-responsive NPY neurons resided in the ventromedial ARC, facing the median eminence (ME), and were surrounded by albumin immunoreactivity, suggesting that they are located outside the blood-brain barrier (BBB). In both normally fed and high-fat diet (HFD) obese animals, CNTF activated extracellular signal-regulated kinase signaling in ME β1- and β2-tanycytes, an effect that has been linked to the promotion of leptin entry into the brain. Accordingly, compared to the animals treated with leptin, mice treated with leptin/CNTF showed: (i) a significantly greater leptin content in hypothalamic protein extracts; (ii) a significant increase in phospho-STAT3 (P-STAT3)-positive neurons in the ARC and the ventromedial hypothalamic nucleus of normally fed mice; and (iii) a significantly increased number of P-STAT3-positive neurons in the ARC and dorsomedial hypothalamic nucleus of HFD obese mice. Collectively, these data suggest that exogenously administered CNTF reduces food intake by exerting a leptin-like action on distinctive NPY ARC neurons and by promoting leptin signaling in hypothalamic feeding centers. |
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| institution | Directory Open Access Journal |
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| last_indexed | 2024-12-12T23:43:23Z |
| publishDate | 2020-05-01 |
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| spelling | doaj.art-150675ed16944a1eb360b3265d4e23d92022-12-22T00:07:01ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022020-05-011410.3389/fncel.2020.00140542699Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse HypothalamusWiebe Venema0Ilenia Severi1Jessica Perugini2Eleonora Di Mercurio3Marco Mainardi4Margherita Maffei5Saverio Cinti6Saverio Cinti7Antonio Giordano8Section of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, Ancona, ItalySection of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, Ancona, ItalySection of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, Ancona, ItalySection of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, Ancona, ItalyInstitute of Neuroscience, National Research Council, Pisa, ItalyInstitute of Neuroscience, National Research Council, Pisa, ItalySection of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, Ancona, ItalyCenter of Obesity, Università Politecnica delle Marche-United Hospitals, Ancona, ItalySection of Neuroscience and Cell Biology, Department of Experimental and Clinical Medicine, Università Politecnica Delle Marche, Ancona, ItalyIn humans and experimental animals, the administration of ciliary neurotrophic factor (CNTF) reduces food intake and body weight. To gain further insights into the mechanism(s) underlying its satiety effect, we: (i) evaluated the CNTF-dependent activation of the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway in mouse models where neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) neurons can be identified by green fluorescent protein (GFP); and (ii) assessed whether CNTF promotes leptin signaling in hypothalamic feeding centers. Immunohistochemical experiments enabled us to establish that intraperitoneal injection of mouse recombinant CNTF activated the JAK2-STAT3 pathway in a substantial proportion of arcuate nucleus (ARC) NPY neurons (18.68% ± 0.60 in 24-h fasted mice and 25.50% ± 1.17 in fed mice) but exerted a limited effect on POMC neurons (4.15% ± 0.33 in 24-h fasted mice and 2.84% ± 0.45 in fed mice). CNTF-responsive NPY neurons resided in the ventromedial ARC, facing the median eminence (ME), and were surrounded by albumin immunoreactivity, suggesting that they are located outside the blood-brain barrier (BBB). In both normally fed and high-fat diet (HFD) obese animals, CNTF activated extracellular signal-regulated kinase signaling in ME β1- and β2-tanycytes, an effect that has been linked to the promotion of leptin entry into the brain. Accordingly, compared to the animals treated with leptin, mice treated with leptin/CNTF showed: (i) a significantly greater leptin content in hypothalamic protein extracts; (ii) a significant increase in phospho-STAT3 (P-STAT3)-positive neurons in the ARC and the ventromedial hypothalamic nucleus of normally fed mice; and (iii) a significantly increased number of P-STAT3-positive neurons in the ARC and dorsomedial hypothalamic nucleus of HFD obese mice. Collectively, these data suggest that exogenously administered CNTF reduces food intake by exerting a leptin-like action on distinctive NPY ARC neurons and by promoting leptin signaling in hypothalamic feeding centers.https://www.frontiersin.org/article/10.3389/fncel.2020.00140/fullarcuate nucleusAgRP neuronsNPY neuronstanycytesmedian eminenceobesity |
| spellingShingle | Wiebe Venema Ilenia Severi Jessica Perugini Eleonora Di Mercurio Marco Mainardi Margherita Maffei Saverio Cinti Saverio Cinti Antonio Giordano Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus Frontiers in Cellular Neuroscience arcuate nucleus AgRP neurons NPY neurons tanycytes median eminence obesity |
| title | Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus |
| title_full | Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus |
| title_fullStr | Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus |
| title_full_unstemmed | Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus |
| title_short | Ciliary Neurotrophic Factor Acts on Distinctive Hypothalamic Arcuate Neurons and Promotes Leptin Entry Into and Action on the Mouse Hypothalamus |
| title_sort | ciliary neurotrophic factor acts on distinctive hypothalamic arcuate neurons and promotes leptin entry into and action on the mouse hypothalamus |
| topic | arcuate nucleus AgRP neurons NPY neurons tanycytes median eminence obesity |
| url | https://www.frontiersin.org/article/10.3389/fncel.2020.00140/full |
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