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Camptothecin effectively treats obesity in mice through GDF15 induction
Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous inductio...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870521/ https://www.ncbi.nlm.nih.gov/pubmed/35202387 http://dx.doi.org/10.1371/journal.pbio.3001517 |
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author | Lu, Jun Feng Zhu, Meng Qing Xie, Bao Cai Shi, Xiao Chen Liu, Huan Zhang, Rui Xin Xia, Bo Wu, Jiang Wei |
author_facet | Lu, Jun Feng Zhu, Meng Qing Xie, Bao Cai Shi, Xiao Chen Liu, Huan Zhang, Rui Xin Xia, Bo Wu, Jiang Wei |
author_sort | Lu, Jun Feng |
collection | PubMed |
description | Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15’s anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15’s specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway. |
format | Online Article Text |
id | pubmed-8870521 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-88705212022-02-25 Camptothecin effectively treats obesity in mice through GDF15 induction Lu, Jun Feng Zhu, Meng Qing Xie, Bao Cai Shi, Xiao Chen Liu, Huan Zhang, Rui Xin Xia, Bo Wu, Jiang Wei PLoS Biol Research Article Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15’s anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15’s specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway. Public Library of Science 2022-02-24 /pmc/articles/PMC8870521/ /pubmed/35202387 http://dx.doi.org/10.1371/journal.pbio.3001517 Text en © 2022 Lu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Lu, Jun Feng Zhu, Meng Qing Xie, Bao Cai Shi, Xiao Chen Liu, Huan Zhang, Rui Xin Xia, Bo Wu, Jiang Wei Camptothecin effectively treats obesity in mice through GDF15 induction |
title | Camptothecin effectively treats obesity in mice through GDF15 induction |
title_full | Camptothecin effectively treats obesity in mice through GDF15 induction |
title_fullStr | Camptothecin effectively treats obesity in mice through GDF15 induction |
title_full_unstemmed | Camptothecin effectively treats obesity in mice through GDF15 induction |
title_short | Camptothecin effectively treats obesity in mice through GDF15 induction |
title_sort | camptothecin effectively treats obesity in mice through gdf15 induction |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870521/ https://www.ncbi.nlm.nih.gov/pubmed/35202387 http://dx.doi.org/10.1371/journal.pbio.3001517 |
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