Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes
Bone morphogenetic protein (BMP)-9, a member of the TGFβ-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Idioma: | inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/107179 |
| Acceso en línea: | https://hdl.handle.net/20.500.14352/107179 |
| Access Level: | acceso abierto |
| Palabra clave: | 577.1 577.2 Diabetes BMP-9 GDF2 Obesity Liver steatosis Biología molecular (Farmacia) Bioquímica (Farmacia) 24 Ciencias de la Vida |
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Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetesStephan DrexlerCai, ChenHartmann, Anna-LenaMoch, DeniseGaitantzi, HaristiNey, TheresaKraemer, MalinChu, YuanZheng, YuweiRahbari, MohammadTreffs, AnnalenaReiser, AlenaLenoir, BénédicteValous, Nektarios A.Jäger, DirkBirgin, EmrullahSawant, Tejas A.Li, QiXu, KeshuDong, LingyueOtto, MirkoItzel, TimoTeufel, AndreasGretz, NorbertHawinkels, Lukas J.A.C.Sánchez Muñoz, AranzazuHerrera González, Blanca MaríaSchubert, RudolfMoshage, HanReissfelder, ChristophEbert, Matthias P.A.Rahbari, Nuh N.Breitkopf-Heinlein, Katja577.1577.2DiabetesBMP-9GDF2ObesityLiver steatosisBiología molecular (Farmacia)Bioquímica (Farmacia)24 Ciencias de la VidaBone morphogenetic protein (BMP)-9, a member of the TGFβ-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients’ samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis.ElsevierUniversidad Complutense de Madrid20232023-01-0120232023-01-01journal articlehttp://purl.org/coar/resource_type/c_6501AMhttp://purl.org/coar/version/c_ab4af688f83e57aainfo:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/107179reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1071792026-06-02T12:44:21Z |
| dc.title.none.fl_str_mv |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes |
| title |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes |
| spellingShingle |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes Stephan Drexler 577.1 577.2 Diabetes BMP-9 GDF2 Obesity Liver steatosis Biología molecular (Farmacia) Bioquímica (Farmacia) 24 Ciencias de la Vida |
| title_short |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes |
| title_full |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes |
| title_fullStr |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes |
| title_full_unstemmed |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes |
| title_sort |
Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes |
| dc.creator.none.fl_str_mv |
Stephan Drexler Cai, Chen Hartmann, Anna-Lena Moch, Denise Gaitantzi, Haristi Ney, Theresa Kraemer, Malin Chu, Yuan Zheng, Yuwei Rahbari, Mohammad Treffs, Annalena Reiser, Alena Lenoir, Bénédicte Valous, Nektarios A. Jäger, Dirk Birgin, Emrullah Sawant, Tejas A. Li, Qi Xu, Keshu Dong, Lingyue Otto, Mirko Itzel, Timo Teufel, Andreas Gretz, Norbert Hawinkels, Lukas J.A.C. Sánchez Muñoz, Aranzazu Herrera González, Blanca María Schubert, Rudolf Moshage, Han Reissfelder, Christoph Ebert, Matthias P.A. Rahbari, Nuh N. Breitkopf-Heinlein, Katja |
| author |
Stephan Drexler |
| author_facet |
Stephan Drexler Cai, Chen Hartmann, Anna-Lena Moch, Denise Gaitantzi, Haristi Ney, Theresa Kraemer, Malin Chu, Yuan Zheng, Yuwei Rahbari, Mohammad Treffs, Annalena Reiser, Alena Lenoir, Bénédicte Valous, Nektarios A. Jäger, Dirk Birgin, Emrullah Sawant, Tejas A. Li, Qi Xu, Keshu Dong, Lingyue Otto, Mirko Itzel, Timo Teufel, Andreas Gretz, Norbert Hawinkels, Lukas J.A.C. Sánchez Muñoz, Aranzazu Herrera González, Blanca María Schubert, Rudolf Moshage, Han Reissfelder, Christoph Ebert, Matthias P.A. Rahbari, Nuh N. Breitkopf-Heinlein, Katja |
| author_role |
author |
| author2 |
Cai, Chen Hartmann, Anna-Lena Moch, Denise Gaitantzi, Haristi Ney, Theresa Kraemer, Malin Chu, Yuan Zheng, Yuwei Rahbari, Mohammad Treffs, Annalena Reiser, Alena Lenoir, Bénédicte Valous, Nektarios A. Jäger, Dirk Birgin, Emrullah Sawant, Tejas A. Li, Qi Xu, Keshu Dong, Lingyue Otto, Mirko Itzel, Timo Teufel, Andreas Gretz, Norbert Hawinkels, Lukas J.A.C. Sánchez Muñoz, Aranzazu Herrera González, Blanca María Schubert, Rudolf Moshage, Han Reissfelder, Christoph Ebert, Matthias P.A. Rahbari, Nuh N. Breitkopf-Heinlein, Katja |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidad Complutense de Madrid |
| dc.subject.none.fl_str_mv |
577.1 577.2 Diabetes BMP-9 GDF2 Obesity Liver steatosis Biología molecular (Farmacia) Bioquímica (Farmacia) 24 Ciencias de la Vida |
| topic |
577.1 577.2 Diabetes BMP-9 GDF2 Obesity Liver steatosis Biología molecular (Farmacia) Bioquímica (Farmacia) 24 Ciencias de la Vida |
| description |
Bone morphogenetic protein (BMP)-9, a member of the TGFβ-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients’ samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 2023-01-01 2023 2023-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 AM http://purl.org/coar/version/c_ab4af688f83e57aa |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/20.500.14352/107179 |
| url |
https://hdl.handle.net/20.500.14352/107179 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
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open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
| dc.format.none.fl_str_mv |
application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
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Elsevier |
| dc.source.none.fl_str_mv |
reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM) |
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Universidad Complutense de Madrid (UCM) |
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Docta Complutense |
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Docta Complutense |
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| repository.mail.fl_str_mv |
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1869405283997974528 |
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15,811543 |