RT Journal Article
T1 Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes
A1 Stephan Drexler, 
A1 Cai, Chen
A1 Hartmann, Anna-Lena
A1 Moch, Denise
A1 Gaitantzi, Haristi
A1 Ney, Theresa
A1 Kraemer, Malin
A1 Chu, Yuan
A1 Zheng, Yuwei
A1 Rahbari, Mohammad
A1 Treffs, Annalena
A1 Reiser, Alena
A1 Lenoir, Bénédicte
A1 Valous, Nektarios A.
A1 Jäger, Dirk
A1 Birgin, Emrullah
A1 Sawant, Tejas A.
A1 Li, Qi
A1 Xu, Keshu
A1 Dong, Lingyue
A1 Otto, Mirko
A1 Itzel, Timo
A1 Teufel, Andreas
A1 Gretz, Norbert
A1 Hawinkels, Lukas J.A.C.
A1 Sánchez Muñoz, Aranzazu
A1 Herrera González, Blanca María
A1 Schubert, Rudolf
A1 Moshage, Han
A1 Reissfelder, Christoph
A1 Ebert, Matthias P.A.
A1 Rahbari, Nuh N.
A1 Breitkopf-Heinlein, Katja
AB 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 thatincreased 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.
PB Elsevier
SN 0303-7207
YR 2023
FD 2023-06
LK https://hdl.handle.net/20.500.14352/107179
UL https://hdl.handle.net/20.500.14352/107179
LA eng
NO Drexler, Stephan, et al. «Intestinal BMP-9 Locally Upregulates FGF19 and Is down-Regulated in Obese Patients with Diabetes». Molecular and Cellular Endocrinology, vol. 570, junio de 2023, p. 111934. DOI.org (Crossref), https://doi.org/10.1016/j.mce.2023.111934.
NO German Research Foundation
DS Docta Complutense
RD 11 abr 2025