Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway
Abstract Background Clinical research has identified stomach dysmotility as a common feature of obesity. However, the specific mechanisms driving gastric emptying dysfunction in patients with obesity remain largely unknown. In this study, we investigated potential mechanisms by focusing on the homeo...
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BMC
2025-07-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-025-01163-5 |
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| author | Sanaa Dekkar Kamilia Mahloul Amandine Falco Karidia Konate Romane Pisteur Sarah Maurel Laurent Maïmoun Norbert Chauvet Prisca Boisguérin David Nocca Ariane Sultan Florian Pallot Guillaume Walther Nicolas Cenac Cyril Breuker Sandrine Faure Pascal de Santa Barbara |
| author_facet | Sanaa Dekkar Kamilia Mahloul Amandine Falco Karidia Konate Romane Pisteur Sarah Maurel Laurent Maïmoun Norbert Chauvet Prisca Boisguérin David Nocca Ariane Sultan Florian Pallot Guillaume Walther Nicolas Cenac Cyril Breuker Sandrine Faure Pascal de Santa Barbara |
| author_sort | Sanaa Dekkar |
| collection | DOAJ |
| description | Abstract Background Clinical research has identified stomach dysmotility as a common feature of obesity. However, the specific mechanisms driving gastric emptying dysfunction in patients with obesity remain largely unknown. In this study, we investigated potential mechanisms by focusing on the homeostasis of gastric smooth muscle. Methods An obese mouse model was established using a high-fat diet (HFD). Immunofluorescence analysis and Western blotting were employed to assess smooth muscle status using stage-specific markers. An in vitro culture model of differentiated human gastric smooth muscle cells (SMCs) was treated with lipids, siRNA-peptide-based nanoparticles and pharmaceutical compounds. Global lipidomic and RNA sequencing analyses were performed. The findings were evaluated in patients with obesity, using gastric samples from individuals who underwent sleeve gastrectomy, to evaluate their clinical relevance. Results The smooth muscle layers in gastric tissue from both mice fed on a HFD as well as patients with obesity exhibited altered differentiation status. Treatment of differentiated human gastric SMCs with lipids phenocopies these alterations and is associated with increased expression of PDK4 and ANGPTL4. Inhibition of PDK4 or ANGPTL4 upregulation prevents these lipid-induced modifications. PPARD activation stimulates PDK4 and ANGPTL4 upregulation, leading to SMC dedifferentiation. Notably, PDK4 and ANGPTL4 levels correlate with immaturity and alteration of gastric smooth muscle in patients with obesity. Conclusions Obesity triggers a phenotypic change in gastric SMCs, driven by the activation of the PPARD/PDK4/ANGPTL4 pathway. These mechanistic insights offer potential biomarkers for diagnosing stomach dysmotility in patients with obesity. |
| format | Article |
| id | doaj-art-9390a6f153da42448857b81900e7d2b2 |
| institution | Kabale University |
| issn | 1423-0127 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Journal of Biomedical Science |
| spelling | doaj-art-9390a6f153da42448857b81900e7d2b22025-08-20T04:03:02ZengBMCJournal of Biomedical Science1423-01272025-07-0132112010.1186/s12929-025-01163-5Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathwaySanaa Dekkar0Kamilia Mahloul1Amandine Falco2Karidia Konate3Romane Pisteur4Sarah Maurel5Laurent Maïmoun6Norbert Chauvet7Prisca Boisguérin8David Nocca9Ariane Sultan10Florian Pallot11Guillaume Walther12Nicolas Cenac13Cyril Breuker14Sandrine Faure15Pascal de Santa Barbara16PHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSIRSD, INSERM, INRAe, ENVT, UPS, University of ToulousePHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSDepartment of Digestive Surgery, University Hospital of MontpellierPHYMEDEXP, University of Montpellier, INSERM, CNRSLAPEC, University of AvignonLAPEC, University of AvignonIRSD, INSERM, INRAe, ENVT, UPS, University of ToulousePHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSPHYMEDEXP, University of Montpellier, INSERM, CNRSAbstract Background Clinical research has identified stomach dysmotility as a common feature of obesity. However, the specific mechanisms driving gastric emptying dysfunction in patients with obesity remain largely unknown. In this study, we investigated potential mechanisms by focusing on the homeostasis of gastric smooth muscle. Methods An obese mouse model was established using a high-fat diet (HFD). Immunofluorescence analysis and Western blotting were employed to assess smooth muscle status using stage-specific markers. An in vitro culture model of differentiated human gastric smooth muscle cells (SMCs) was treated with lipids, siRNA-peptide-based nanoparticles and pharmaceutical compounds. Global lipidomic and RNA sequencing analyses were performed. The findings were evaluated in patients with obesity, using gastric samples from individuals who underwent sleeve gastrectomy, to evaluate their clinical relevance. Results The smooth muscle layers in gastric tissue from both mice fed on a HFD as well as patients with obesity exhibited altered differentiation status. Treatment of differentiated human gastric SMCs with lipids phenocopies these alterations and is associated with increased expression of PDK4 and ANGPTL4. Inhibition of PDK4 or ANGPTL4 upregulation prevents these lipid-induced modifications. PPARD activation stimulates PDK4 and ANGPTL4 upregulation, leading to SMC dedifferentiation. Notably, PDK4 and ANGPTL4 levels correlate with immaturity and alteration of gastric smooth muscle in patients with obesity. Conclusions Obesity triggers a phenotypic change in gastric SMCs, driven by the activation of the PPARD/PDK4/ANGPTL4 pathway. These mechanistic insights offer potential biomarkers for diagnosing stomach dysmotility in patients with obesity.https://doi.org/10.1186/s12929-025-01163-5Smooth muscleObesityStomachImmaturityPDK4/ANGPTL4/PPARD pathway |
| spellingShingle | Sanaa Dekkar Kamilia Mahloul Amandine Falco Karidia Konate Romane Pisteur Sarah Maurel Laurent Maïmoun Norbert Chauvet Prisca Boisguérin David Nocca Ariane Sultan Florian Pallot Guillaume Walther Nicolas Cenac Cyril Breuker Sandrine Faure Pascal de Santa Barbara Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway Journal of Biomedical Science Smooth muscle Obesity Stomach Immaturity PDK4/ANGPTL4/PPARD pathway |
| title | Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway |
| title_full | Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway |
| title_fullStr | Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway |
| title_full_unstemmed | Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway |
| title_short | Obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the PPARD/PDK4/ANGPTL4 pathway |
| title_sort | obesity induces phenotypic switching of gastric smooth muscle cells through the activation of the ppard pdk4 angptl4 pathway |
| topic | Smooth muscle Obesity Stomach Immaturity PDK4/ANGPTL4/PPARD pathway |
| url | https://doi.org/10.1186/s12929-025-01163-5 |
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