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1. Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH

Author

L’homme, Laurent, Sermikli, Benan Pelin, Haas, Joel T., Fleury, Sébastien, Quemener, Sandrine, Guinot, Valentine, Barreby, Emelie, Esser, Nathalie, Caiazzo, Robert, Verkindt, Hélène, Legendre, Benjamin, Raverdy, Violeta, Cheval, Lydie, Paquot, Nicolas, Piette, Jacques, Legrand-Poels, Sylvie, Aouadi, Myriam, Pattou, François, Staels, Bart, and Dombrowicz, David

Published
2024
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2. Unravelling the sex-specific diversity and functions of adrenal gland macrophages

Author

Dolfi, Bastien, Gallerand, Alexandre, Firulyova, Maria M., Xu, Yingzheng, Merlin, Johanna, Dumont, Adélie, Castiglione, Alexia, Vaillant, Nathalie, Quemener, Sandrine, Gerke, Heidi, Stunault, Marion I., Schrank, Patricia R., Kim, Seung-Hyeon, Zhu, Alisha, Ding, Jie, Gilleron, Jerome, Magnone, Virginie, Barbry, Pascal, Dombrowicz, David, Duranton, Christophe, Wakkach, Abdelilah, Blin-Wakkach, Claudine, Becher, Burkhard, Pagnotta, Sophie, Argüello, Rafael J., Rantakari, Pia, Chakarov, Svetoslav, Ginhoux, Florent, Zaitsev, Konstantin, Kim, Ki-Wook, Yvan-Charvet, Laurent, Guinamard, Rodolphe R., Williams, Jesse W., and Ivanov, Stoyan

Published
2022
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4. Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR

Author

Mogilenko, Denis A., Haas, Joel T., L’homme, Laurent, Fleury, Sébastien, Quemener, Sandrine, Levavasseur, Matthieu, Becquart, Coralie, Wartelle, Julien, Bogomolova, Alexandra, Pineau, Laurent, Molendi-Coste, Olivier, Lancel, Steve, Dehondt, Hélène, Gheeraert, Celine, Melchior, Aurelie, Dewas, Cédric, Nikitin, Artemii, Pic, Samuel, Rabhi, Nabil, Annicotte, Jean-Sébastien, Oyadomari, Seiichi, Velasco-Hernandez, Talia, Cammenga, Jörg, Foretz, Marc, Viollet, Benoit, Vukovic, Milica, Villacreces, Arnaud, Kranc, Kamil, Carmeliet, Peter, Marot, Guillemette, Boulter, Alexis, Tavernier, Simon, Berod, Luciana, Longhi, Maria P., Paget, Christophe, Janssens, Sophie, Staumont-Sallé, Delphine, Aksoy, Ezra, Staels, Bart, and Dombrowicz, David

Published
2019
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9. Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride‐rich lipoprotein metabolism

Author

Deprince, Audrey, primary, Hennuyer, Nathalie, additional, Kooijman, Sander, additional, Pronk, Amanda C. M., additional, Baugé, Eric, additional, Lienard, Viktor, additional, Verrijken, An, additional, Dirinck, Eveline, additional, Vonghia, Luisa, additional, Woitrain, Eloïse, additional, Kloosterhuis, Niels J., additional, Marez, Eléonore, additional, Jacquemain, Pauline, additional, Wolters, Justina C., additional, Lalloyer, Fanny, additional, Eberlé, Delphine, additional, Quemener, Sandrine, additional, Vallez, Emmanuelle, additional, Tailleux, Anne, additional, Kouach, Mostafa, additional, Goossens, Jean‐Francois, additional, Raverdy, Violeta, additional, Derudas, Bruno, additional, Kuivenhoven, Jan Albert, additional, Croyal, Mikaël, additional, van de Sluis, Bart, additional, Francque, Sven, additional, Pattou, François, additional, Rensen, Patrick C. N., additional, Staels, Bart, additional, and Haas, Joel T., additional

Published
2022
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10. Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride‐rich lipoprotein metabolism.

Author

Deprince, Audrey, Hennuyer, Nathalie, Kooijman, Sander, Pronk, Amanda C. M., Baugé, Eric, Lienard, Viktor, Verrijken, An, Dirinck, Eveline, Vonghia, Luisa, Woitrain, Eloïse, Kloosterhuis, Niels J., Marez, Eléonore, Jacquemain, Pauline, Wolters, Justina C., Lalloyer, Fanny, Eberlé, Delphine, Quemener, Sandrine, Vallez, Emmanuelle, Tailleux, Anne, and Kouach, Mostafa

Published
2023
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11. Hypothalamic bile acid-TGR5 signaling protects from obesity

Author

Castellanos-Jankiewicz, Ashley, Guzmán-Quevedo, Omar, Fénelon, Valérie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlène, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Bäckhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, and Cota, Daniela

Published
2021
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12. Short Article Hypothalamic bile acid-TGR5 signaling protects from obesity

Author

Castellanos-Jankiewicz, Ashley, Guzman-Quevedo, Omar, Fenelon, Valerie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlene, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Backhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, Cota, Daniela, Castellanos-Jankiewicz, Ashley, Guzman-Quevedo, Omar, Fenelon, Valerie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlene, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Backhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, and Cota, Daniela

Abstract

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet induced obesity.

Published
2021

14. Metabolic and innate immune cues merge into a specific inflammatory response via unfolded proteinresponse (UPR)

Author

Mogilenko, Denis, Haas, Joël, L'Homme, Laurent, Fleury, Sébastien, Quemener, Sandrine, Levavasseur, Matthieu, Becquart, Coralie, Wartelle, Julien, Bogomolova, Alexandra, Pineau, Laurent, Molendi-Coste, Olivier, Lancel, Steve, Dehondt, Hélène, Gheeraert, Céline, Melchior, Aurélie, Dewas, Cédric, Nikitin, Artemii, Pic, Samuel, Rabhi, Nabil, Annicotte, Jean-Sébastien, Oyadomari, Seiichi, Velasco-Hernandez, Talia, Cammenga, Jörg, Foretz, Marc, Viollet, Benoit, Vukovic, Milica, Villacreces, Arnaud, Kranc, Kamil, Carmeliet, Peter, Marot, Guillemette, Boulter, Alexis, Tavernier, Simon, Berod, Luciana, Longhi, Maria, Paget, Christophe, Janssens, Sophie, Staumont-Sallé, Delphine, Aksoy, Ezra, Staels, Bart, Dombrowicz, David, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Fujii Memorial Institute of Medical Sciences [Tokushima, Japan] (Institute of Advanced Medical Sciences), Tokushima University, Department of Hematology [Linköping, Sweden] (Institute for Clinical and Experimental Medicine), Linköping University (LIU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Centre for Haemato-Oncology [London, UK] (Barts Cancer Institute), Queen Mary University of London (QMUL), Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium], VIB-KU Leuven Center for Brain & Disease Research [Leuven, Belgium], Laboratory of Angiogenesis and Vascular Metabolism [Leuven, Belgium] (VIB-CCB), Department of Oncology [Leuven, Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), MOdel for Data Analysis and Learning (MODAL), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille)-Université de Lille, Sciences et Technologies, University of Florida [Gainesville] (UF), Unit of Immunoregulation and Mucosal Immunology [Ghent, Belgium], VIB Inflammation Research Center [Ghent, Belgium], Hannover Medical School [Hannover] (MHH), The William Harvey Research Institute [London, UK] (NIHR Barts Biomedical Research Centre), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), ER Stress and Inflammation [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Département de Dermatologie [CHRU Lille], Centre for Biochemical Pharmacology [London, UK] (William Harvey Research Institute), This work was supported in part by grants from ANR and the European Union (EGID ANR-10-LABX-46 to B.S. and D.D. and ANR-17-CE15-0030-02 to B.V.), a National Psoriasis Foundation (USA) Early Career Research Grant (to D.A.M.), an EMBO Long-Term Fellowship (to J.T.H.), an MRC grant (MR/M023230/1 to E.A.), and CRUK grants (C29967/A14633 and C29967/A26787 to K.K.). B.S. is recipient of an ERC advanced grant (ERC-2016-AdG-694717)., We thank members of the Bart Staels lab for help with experiments, Jean-Claude Sirard (Institut Pasteur de Lille, France), Juan R. Cubillos-Ruiz and Laurie H. Glimcher (Weill Cornell Medical College, New York, USA), Eik Hoffmann (Institut Pasteur de Lille, France) for mice, and Morten Danielsen and Lea Johnsen (MS-Omics, Copenhagen, Denmark) for assistance with LC-MS and GC-MS., Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire Paul Painlevé (LPP), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-École polytechnique universitaire de Lille (Polytech Lille), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE15-0030,MetaTreg,Métabolisme cellulaire des Treg dans le controle des maladies inflammatoires chroniques(2017), Laboratoire Paul Painlevé - UMR 8524 (LPP), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université de Lille, Sciences et Technologies-Inria Lille - Nord Europe, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-École polytechnique universitaire de Lille (Polytech Lille), and Dupuis, Christine

Subjects
mtROS, [SDV.IMM] Life Sciences [q-bio]/Immunology, hexokinase, UPR, psoriasis, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, glycolysis, fatty acids, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, IL-23, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, metabolic reprogramming, [SDV.IMM]Life Sciences [q-bio]/Immunology, dendritic cells, innate immunity, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

Erratum in : Metabolic and Innate Immune Cues Merge into a Specific Inflammatory Response via the UPR. [Cell. 2019]; International audience; Innate immune responses are intricately linked with intracellular metabolism of myeloid cells. Toll-likereceptor (TLR) stimulation shifts intracellular metabolism toward glycolysis, while anti-inflammatorysignals depend on enhanced mitochondrial respiration. How exogenous metabolic signals affect theimmune response is unknown. We demonstrate that TLR-dependent responses of dendritic cells (DC)are exacerbated by a high fatty acid (FA) metabolic environment. FA suppress the TLR-inducedhexokinase activity and perturb tricarboxylic acid cycle metabolism. These metabolic changesenhance mitochondrial reactive oxygen species (mtROS) production and, in turn, the unfolded proteinresponse (UPR) leading to a distinct transcriptomic signature, with IL-23 as hallmark. Interestingly,chemical or genetic suppression of glycolysis was sufficient to induce this specific immune response.Conversely, reducing mtROS production or DC-specific deficiency in XBP1 attenuated IL-23expression and skin inflammation in an IL-23-dependent model of psoriasis. Thus, fine-tuning of innateimmunity depends on optimization of metabolic demands and minimization of mtROS-induced UPR.

Published
2019
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15. Psoriasis-like inflammation in K14PPARu03b2/u03b4 transgenic mice selectively overexpressing PPARu03b2/u03b4 in keratinocytes.

Author

Dezoteux, Frédéric, Quemener , Sandrine, and Fleury , Sébastien

Abstract

Psoriasis is an inflammatory skin disease affecting 2-3% of the general population and whose precise aetiology remains poorly understood. Several lines of evidence suggest that the nuclear receptor peroxisome proliferator activator (PPAR) u03b2/u03b4, known to regulate epithelial differentiation, proliferation, wound healing and epidermal barrier recovery, contributes to psoriasis pathogenesis. It is unclear, however, whether activation of PPAR u03b2/u03b4 is sufficient to trigger psoriasis-like inflammation.Overexpression of PPARu03b2/u03b4 in keratinocytes in mice leads to death 8 days after birth despite food intake and integrity of the skin barrier. The reason of lethality remains to be elucidated. K14PPARu03b2/u03b4 Tg mice developed inflammatory cutaneous lesions 5 days after birth, that worsened with time. These skin lesions shared similar clinical, histological and immunological features with human psoriasis. However, some disparities with human lesions were observed such as for some cytokine (IL-4, IL-33) mRNA profiles and immunologic responses. T-cells, commonly found in psoriasis lesions, were rare in skin of K14PPARu03b2/u03b4 Tg mice, probably as a consequence of an immature immune system at 5 days of life. Microarray analysis showed a similar transcript profile in K14PPARu03b2/u03b4 Tg mice compared to human psoriasis. Though K14PPARu03b2/u03b4 Tg mice may represent an interesting experimental model to better understand the pathophysiology of the early stages of human psoriasis.

Published
2017

16. Surexpression kératinocytaire de PPARß/δ chez la souris : un modèle de psoriasis ?

Author

Dezoteux, Frédéric, primary, Quemener, Sandrine, additional, Fleury, Sébastien, additional, Molendi-Coste, Olivier, additional, Pineau, Laurent, additional, Mogilenko, Denis, additional, Dhalluin, Quentin, additional, Gheeraert, Céline, additional, Lefebvre, Philippe, additional, Staels, Bart, additional, Dombrowicz, David, additional, Gross, Barbara, additional, and Staumont-Sallé, Delphine, additional

Published
2016
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17. Deletion of the nuclear receptor RORα in macrophages does not modify the development of obesity, insulin resistance and NASH.

Author

L'homme, Laurent, Sermikli, Benan Pelin, Molendi-Coste, Olivier, Fleury, Sébastien, Quemener, Sandrine, Le Maître, Mathilde, Joseph, Marie-Laure, Pineau, Laurent, Duhem, Christian, Gross, Barbara, Vallez, Emmanuelle, Tailleux, Anne, Staels, Bart, and Dombrowicz, David

Subjects
NUCLEAR receptors (Biochemistry), MACROPHAGES, INSULIN resistance, OBESITY, PROTEIN expression
Abstract

Retinoic acid receptor-related orphan receptor-alpha (RORα) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for RORα in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of RORα in obesity and IR, we independently generated a macrophage RORα-deficient mouse line. We report that RORα deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an effect on NASH development upon HFD feeding nor in the more severe and obesity-independent choline-deficient, L-amino acid-defined diet model. Our results therefore show that RORα deletion in macrophages does not alter the development of obesity and IR and question its role in NASH. [ABSTRACT FROM AUTHOR]

Published
2020
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18. Short Article Hypothalamic bile acid-TGR5 signaling protects from obesity

Author

Castellanos-Jankiewicz, Ashley, Guzman-Quevedo, Omar, Fenelon, Valerie S., Zizzari, Philippe, Quarta, Carmelo, Bellocchio, Luigi, Tailleux, Anne, Charton, Julie, Fernandois, Daniela, Henricsson, Marcus, Piveteau, Catherine, Simon, Vincent, Allard, Camille, Quemener, Sandrine, Guinot, Valentine, Hennuyer, Nathalie, Perino, Alessia, Duveau, Alexia, Maitre, Marlene, Leste-Lasserre, Thierry, Clark, Samantha, Dupuy, Nathalie, Cannich, Astrid, Gonzales, Delphine, Deprez, Benoit, Mithieux, Gilles, Dombrowicz, David, Backhed, Fredrik, Prevot, Vincent, Marsicano, Giovanni, Staels, Bart, Schoonjans, Kristina, and Cota, Daniela

Subjects
ENERGY-EXPENDITURE, GASTRIC BYPASS, THERMOGENESIS, energy-expenditure, neurons, thermogenesis, MOUSE, GLUCOSE, SERUM, ACTIVATION, secretion, SECRETION, activation, glucose, gastric bypass, ACID RECEPTOR TGR5, NEURONS, acid receptor tgr5, serum, mouse
Abstract

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet induced obesity.

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19. Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.

Author

L'homme L, Sermikli BP, Haas JT, Fleury S, Quemener S, Guinot V, Barreby E, Esser N, Caiazzo R, Verkindt H, Legendre B, Raverdy V, Cheval L, Paquot N, Piette J, Legrand-Poels S, Aouadi M, Pattou F, Staels B, and Dombrowicz D

Subjects
Animals, Male, Mice, Humans, Mice, Inbred C57BL, Liver metabolism, Liver pathology, Disease Models, Animal, Signal Transduction, Growth Differentiation Factor 15 metabolism, Growth Differentiation Factor 15 genetics, Obesity metabolism, Obesity pathology, Hepatocytes metabolism, Macrophages metabolism, Adipose Tissue metabolism, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Fatty Liver metabolism, Fatty Liver pathology
Abstract

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels., (© 2024. The Author(s).)

Published
2024
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