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Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs
OBJECTIVE: A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high‐fat diet (HFD) compared with standard diet. METHODS: Serum and cerebrospinal fluid (CS...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593767/ https://www.ncbi.nlm.nih.gov/pubmed/31006983 http://dx.doi.org/10.1002/oby.22465 |
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author | Chmielewski, Alexandra Hubert, Thomas Descamps, Amandine Mazur, Daniele Daoudi, Mehdi Ciofi, Philippe Fontaine, Christian Caiazzo, Robert Pattou, François Prevot, Vincent Pigeyre, Marie |
author_facet | Chmielewski, Alexandra Hubert, Thomas Descamps, Amandine Mazur, Daniele Daoudi, Mehdi Ciofi, Philippe Fontaine, Christian Caiazzo, Robert Pattou, François Prevot, Vincent Pigeyre, Marie |
author_sort | Chmielewski, Alexandra |
collection | PubMed |
description | OBJECTIVE: A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high‐fat diet (HFD) compared with standard diet. METHODS: Serum and cerebrospinal fluid (CSF) leptin concentrations during 10 weeks of HFD versus standard diet and exogenous leptin‐induced STAT3 phosphorylation in the hypothalamus of minipigs were assessed, and the hypothalamic leptin‐sensitive cells were characterized by immunofluorescence. RESULTS: The efficiency of the passage of endogenous blood‐borne leptin into the CSF (measured as the log [CSF:serum leptin ratio]) decreased over time in minipigs fed a HFD (β = –0.04 ± 0.005 per kilogram of weight gain in HFD; P < 0.0001), while it remained stable in minipigs fed a standard diet. However, the ability of peripherally administered leptin to activate its receptor in hypothalamic neurons was preserved in obese minipigs at 10 weeks of HFD. CONCLUSIONS: Together, these data are consistent with the existence of an early‐onset tranport deficiency for endogenous circulating leptin into the brain in individuals developing obesity, preceding the acquisition of hypothalamic leptin resistance. Although additional studies are required to identify the underlying mechanisms, our study paves the way for the development of new preclinical pharmacological models targeting the restoration of the shuttling of peripheral leptin into the central nervous system to manage obesity. |
format | Online Article Text |
id | pubmed-6593767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65937672019-07-10 Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs Chmielewski, Alexandra Hubert, Thomas Descamps, Amandine Mazur, Daniele Daoudi, Mehdi Ciofi, Philippe Fontaine, Christian Caiazzo, Robert Pattou, François Prevot, Vincent Pigeyre, Marie Obesity (Silver Spring) Original Articles OBJECTIVE: A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high‐fat diet (HFD) compared with standard diet. METHODS: Serum and cerebrospinal fluid (CSF) leptin concentrations during 10 weeks of HFD versus standard diet and exogenous leptin‐induced STAT3 phosphorylation in the hypothalamus of minipigs were assessed, and the hypothalamic leptin‐sensitive cells were characterized by immunofluorescence. RESULTS: The efficiency of the passage of endogenous blood‐borne leptin into the CSF (measured as the log [CSF:serum leptin ratio]) decreased over time in minipigs fed a HFD (β = –0.04 ± 0.005 per kilogram of weight gain in HFD; P < 0.0001), while it remained stable in minipigs fed a standard diet. However, the ability of peripherally administered leptin to activate its receptor in hypothalamic neurons was preserved in obese minipigs at 10 weeks of HFD. CONCLUSIONS: Together, these data are consistent with the existence of an early‐onset tranport deficiency for endogenous circulating leptin into the brain in individuals developing obesity, preceding the acquisition of hypothalamic leptin resistance. Although additional studies are required to identify the underlying mechanisms, our study paves the way for the development of new preclinical pharmacological models targeting the restoration of the shuttling of peripheral leptin into the central nervous system to manage obesity. John Wiley and Sons Inc. 2019-04-21 2019-06 /pmc/articles/PMC6593767/ /pubmed/31006983 http://dx.doi.org/10.1002/oby.22465 Text en © 2019 The Authors. Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS) This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Chmielewski, Alexandra Hubert, Thomas Descamps, Amandine Mazur, Daniele Daoudi, Mehdi Ciofi, Philippe Fontaine, Christian Caiazzo, Robert Pattou, François Prevot, Vincent Pigeyre, Marie Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs |
title | Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs |
title_full | Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs |
title_fullStr | Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs |
title_full_unstemmed | Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs |
title_short | Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs |
title_sort | preclinical assessment of leptin transport into the cerebrospinal fluid in diet‐induced obese minipigs |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593767/ https://www.ncbi.nlm.nih.gov/pubmed/31006983 http://dx.doi.org/10.1002/oby.22465 |
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