[en] 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.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
L'homme, Laurent ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France. laurent.l-homme@inserm.fr
Sermikli, Benan Pelin ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
Haas, Joel T ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
Fleury, Sébastien ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
Quemener, Sandrine ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
Guinot, Valentine; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
Barreby, Emelie ; Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Esser, Nathalie ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladies métaboliques ; Université de Liège - ULiège > GIGA > GIGA I3 - Immunometabolism and Nutrition ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques
Caiazzo, Robert ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
Verkindt, Hélène; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
Legendre, Benjamin; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
Raverdy, Violeta; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
Cheval, Lydie; Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France ; CNRS EMR 8228-Unité Métabolisme et Physiologie Rénale, Paris, France
Paquot, Nicolas ; Université de Liège - ULiège > Département des sciences cliniques > Diabétologie, nutrition et maladies métaboliques
Piette, Jacques ; Université de Liège - ULiège > GIGA > GIGA I3 - Virology and Immunology
Legrand, Sylvie ; Université de Liège - ULiège > GIGA > GIGA I3 - Immunometabolism and Nutrition
Aouadi, Myriam ; Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
Pattou, François ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1190-EGID (Translational research in Diabetes), Lille, France
Staels, Bart ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
Dombrowicz, David ; Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France. david.dombrowicz@pasteur-lille.fr
V. Azzu M. Vacca S. Virtue M. Allison A. Vidal-Puig Adipose tissue-liver cross talk in the control of whole-body metabolism: implications in nonalcoholic fatty liver disease Gastroenterology 2020 158 1899 1912 1:CAS:528:DC%2BB3cXosVaisL0%3D 32061598
Y. Geng K.N. Faber V.E. de Meijer H. Blokzijl H. Moshage How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease? Hepatol. Int. 2021 15 21 35 33548031
W.D. Fairlie et al. MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation J. Leukoc. Biol. 1999 65 2 5 1:CAS:528:DyaK1MXjs1yqsA%3D%3D 9886240
V.M. Paralkar et al. Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family J. Biol. Chem. 1998 273 13760 13767 1:CAS:528:DyaK1cXjvVejur8%3D 9593718
Q. Ding et al. Identification of macrophage inhibitory cytokine-1 in adipose tissue and its secretion as an adipokine by human adipocytes Endocrinology 2009 150 1688 1696 1:CAS:528:DC%2BD1MXktVWlsr8%3D 19074584
J.-Y. Hsu et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15 Nature 2017 550 255 259 2017Natur.550.255H 28953886
S.E. Mullican et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates Nat. Med. 2017 23 1150 1157 1:CAS:528:DC%2BC2sXhtl2gu7rE 28846097
L. Yang et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand Nat. Med. 2017 23 1158 1166 1:CAS:528:DC%2BC2sXhtl2gu7rL 28846099
D. Wang et al. GDF15 promotes weight loss by enhancing energy expenditure in muscle Nature 2023 619 143 150 2023Natur.619.143W 1:CAS:528:DC%2BB3sXhtlCnt7fF 37380764 10322716
V.W.W. Tsai Y. Husaini A. Sainsbury D.A. Brown S.N. Breit The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases Cell Metab 2018 28 353 368 1:CAS:528:DC%2BC1cXhs1GqtrbE 30184485
K. Chrysovergis et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism Int. J. Obes. 2005 2014 38 1555 1564 1:CAS:528:DC%2BC2cXls1Kjtrs%3D
H.K. Chung et al. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis J. Cell Biol. 2017 216 149 165 1:CAS:528:DC%2BC2sXptFGrtrs%3D 27986797 5223607
M.R. Bootcov et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily Proc. Natl. Acad. Sci. USA 1997 94 11514 11519 1997PNAS..9411514B 1:CAS:528:DyaK2sXmslaqsr0%3D 9326641 23523
O. Govaere et al. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis Sci. Transl. Med. 2020 12 eaba4448 1:CAS:528:DC%2BB3cXisFSiu7zO 33268509
S. Patel et al. Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice Mol. Metab. 2022 65 101589 1:CAS:528:DC%2BB38XitleqsLvL 36064109 9486046
T. Tran J. Yang J. Gardner Y. Xiong GDF15 deficiency promotes high fat diet-induced obesity in mice PloS One 2018 13 e0201584 30070999 6072047
D. Li H. Zhang Y. Zhong Hepatic GDF15 is regulated by CHOP of the unfolded protein response and alleviates NAFLD progression in obese mice Biochem. Biophys. Res. Commun. 2018 498 388 394 1:CAS:528:DC%2BC1cXkt1Glt7g%3D 28847729
L. Macia et al. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets PloS One 2012 7 e34868 2012PLoSO..734868M 1:CAS:528:DC%2BC38Xmt1ehu7Y%3D 22514681 3325923
I. Dostálová et al. Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet Eur. J. Endocrinol. Eur. Fed. Endocr. Soc. 2009 161 397 404
T. Kempf et al. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial Eur. J. Endocrinol. 2012 167 671 678 1:CAS:528:DC%2BC38XhslSmsLbN 22918303
B.K. Koo et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease Liver Int. Off. J. Int. Assoc. Study Liver 2018 38 695 705 1:CAS:528:DC%2BC1cXmsVamu7o%3D
G. Vila et al. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients Clin. Chem. 2011 57 309 316 1:CAS:528:DC%2BC3MXislaisrg%3D 21164037
J. Kim et al. TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response Nat. Metab. 2021 3 410 427 1:CAS:528:DC%2BB3MXhtlyru7%2FI 33758420
S. Patel et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans Cell Metab 2019 29 707 718.e8 1:CAS:528:DC%2BC1MXovFOrsg%3D%3D 30639358 6408327
X. Chen Y. Tang S. Chen W. Ling Q. Wang IGFBP-2 as a biomarker in NAFLD improves hepatic steatosis: an integrated bioinformatics and experimental study Endocr. Connect. 2021 10 1315 1325 1:CAS:528:DC%2BB3MXislCgt77E 34524971 8562889
L. L’homme et al. Deletion of the nuclear receptor RORα in macrophages does not modify the development of obesity, insulin resistance and NASH Sci. Rep. 2020 10 2020NatSR.1021095L 33273527 7713245
S. Cinti et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans J. Lipid Res. 2005 46 2347 2355 1:CAS:528:DC%2BD2MXhtF2iu7vF 16150820
C.N. Lumeng J.L. Bodzin A.R. Saltiel Obesity induces a phenotypic switch in adipose tissue macrophage polarization J. Clin. Invest. 2007 117 175 184 1:CAS:528:DC%2BD2sXmvV2quw%3D%3D 17200717 1716210
M.A. Cottam H.L. Caslin N.C. Winn A.H. Hasty Multiomics reveals persistence of obesity-associated immune cell phenotypes in adipose tissue during weight loss and weight regain in mice Nat. Commun. 2022 13 2022NatCo.13.2950C 1:CAS:528:DC%2BB38XhsVejsL7L 35618862 9135744
E. Barreby A. Sulen M. Aouadi Glucan-encapsulated siRNA particles (GeRPs) for specific gene silencing in adipose tissue macrophages Methods Mol. Biol. Clifton NJ 2019 1951 49 57 1:CAS:528:DC%2BC1MXitVyksL3F
P.J. Emmerson et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL Nat. Med. 2017 23 1215 1219 1:CAS:528:DC%2BC2sXhtl2gu7rK 28846098
L. Wrobel F.H. Siddiqi D.C. Rubinsztein Transient siRNA-mediated protein knockdown in mouse followed by feeding/starving cycle and liver tissue analysis STAR Protoc. 2021 2 100500 1:CAS:528:DC%2BB38Xhs1Cmu7fL 33997814 8102171
A. Tan R. Prasad C. Lee E.-H. Jho Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease Cell Death Differ 2022 29 1433 1449 1:CAS:528:DC%2BB38XitFKhu7nP 35739255 9345944
Y. Xie Y. Li J. Chen H. Ding X. Zhang Early growth response-1: key mediators of cell death and novel targets for cardiovascular disease therapy Front. Cardiovasc. Med. 2023 10 1162662 1:CAS:528:DC%2BB3sXitlKqsb3L 37057102 10086247
Y. Yang et al. Transcription factor C/EBP homologous protein in health and diseases Front. Immunol. 2017 8 1612 29230213 5712004
A. Osman et al. Identification of genomic binding sites and direct target genes for the transcription factor DDIT3/CHOP Exp. Cell Res. 2023 422 113418 1:CAS:528:DC%2BB38XivFalu7fE 36402425
J.T. Haas et al. Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution Nat. Metab. 2019 1 604 614 1:CAS:528:DC%2BB3cXks1Kku7g%3D 31701087 6837876
E.C. Hsiao et al. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury Mol. Cell. Biol. 2000 20 3742 3751 1:CAS:528:DC%2BD3cXivFyhtbk%3D 10779363 85678
P. Jiang et al. Growth differentiation factor 15 is dispensable for acetaminophen-induced liver injury in mice Basic Clin. Pharmacol. Toxicol. 2023 132 343 353 1:CAS:528:DC%2BB3sXpt1Giug%3D%3D 36602134
V. Dubois et al. Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver Mol. Syst. Biol. 2020 16 e9156 1:CAS:528:DC%2BB3cXhtVKqurbI 32407006 7224309
M. Tsuchiya et al. Interstrain differences in liver injury and one-carbon metabolism in alcohol-fed mice Hepatol. Baltim. Md 2012 56 130 139 1:CAS:528:DC%2BC38XpvVegur8%3D
R.-D. Tian et al. Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury Ann. Hepatol. 2020 19 79 87 1:CAS:528:DC%2BB3cXisFKitLrL 31548168
I. Ben Mosbah et al. Endoplasmic reticulum stress inhibition protects steatotic and non-steatotic livers in partial hepatectomy under ischemia-reperfusion Cell Death Dis. 2010 1 21364657 3032561
D. Uzi et al. CHOP is a critical regulator of acetaminophen-induced hepatotoxicity J. Hepatol. 2013 59 495 503 1:CAS:528:DC%2BC3sXhtVOqsr%2FL 23665281
Y.-E. Lian Y.-N. Bai J.-L. Lai A.-M. Huang Aberrant regulation of autophagy disturbs fibrotic liver regeneration after partial hepatectomy Front. Cell Dev. Biol. 2022 10 1030338 36393837 9644332
D.J. Samuvel et al. Mitochondrial depolarization after acute ethanol treatment drives mitophagy in living mice Autophagy 2022 18 2671 2685 1:CAS:528:DC%2BB38XosFOgtbw%3D 35293288 9629059
X. Bao et al. Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer-Cardiovascular Cohort Diabetologia 2019 62 78 86 1:CAS:528:DC%2BC1cXitVSit7%2FM 30350239
D.A. Brown et al. MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2003 9 2642 2650 1:CAS:528:DC%2BD3sXlt1yrs74%3D
D.A. Brown et al. Concentration in plasma of macrophage inhibitory cytokine-1 and risk of cardiovascular events in women: a nested case-control study Lancet Lond. Engl. 2002 359 2159 2163 1:CAS:528:DC%2BD38XkslGhtr0%3D
O. Benichou et al. Discovery, development, and clinical proof of mechanism of LY3463251, a long-acting GDF15 receptor agonist Cell Metab 2023 35 274 286.e10 1:CAS:528:DC%2BB3sXnvVamuw%3D%3D 36630958
Y. Zhang et al. Activity-balanced GLP-1/GDF15 dual agonist reduces body weight and metabolic disorder in mice and non-human primates Cell Metab 2023 35 287 298.e4 36706758
C. Wang et al. Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan Nat. Commun. 2017 8 2017NatCo..8.2270W 29273768 5741634
R. Caiazzo et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study Ann. Surg. 2014 260 893 898 25379859
V. Raverdy et al. Data-driven subgroups of type 2 diabetes, metabolic response, and renal risk profile after bariatric surgery: a retrospective cohort study Lancet Diabetes Endocrinol. 2022 10 167 176 35148818
D.E. Kleiner et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease Hepatol. Baltim. Md 2005 41 1313 1321
D. Margerie et al. Hepatic transcriptomic signatures of statin treatment are associated with impaired glucose homeostasis in severely obese patients BMC Med. Genomics 2019 12 31159817 6545676
American Diabetes Association. Diagnosis and classification of diabetes mellitus Diabetes Care 2014 37 S81 S90
Rinella, M. E. et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. S0168-8278(23)00418-X https://doi.org/10.1016/j.jhep.2023.06.003 (2023).
N. Esser et al. Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue Diabetologia 2013 56 2487 2497 1:CAS:528:DC%2BC3sXhs1Wit7bN 24013717
L. Cheval et al. Acidosis-induced activation of distal nephron principal cells triggers Gdf15 secretion and adaptive proliferation of intercalated cells Acta Physiol. Oxf. Engl. 2021 232 e13661 1:CAS:528:DC%2BB3MXpsVSrtb8%3D
L. L’homme et al. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages J. Lipid Res. 2013 54 2998 3008 24006511 3793604
I.J. Schippers et al. Immortalized human hepatocytes as a tool for the study of hepatocytic (de-)differentiation Cell Biol. Toxicol. 1997 13 375 386 1:STN:280:DyaK2svktleqtQ%3D%3D 9298258
H.J.M. de Jonge et al. Evidence based selection of housekeeping genes PLoS One 2007 2 e898 2007PLoSO..2.898D 17878933 1976390
F.O. Martinez S. Gordon M. Locati A. Mantovani Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression J. Immunol. Baltim. Md 1950 2006 177 7303 7311 1:CAS:528:DC%2BD28XhtFGrtrbM
T.S.P. Heng M.W. Painter Immunological Genome Project Consortium. The Immunological Genome Project: networks of gene expression in immune cells Nat. Immunol. 2008 9 1091 1094 1:CAS:528:DC%2BD1cXhtFeit7zE 18800157
A. Subramanian et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles Proc. Natl. Acad. Sci. USA 2005 102 15545 15550 2005PNAS.10215545S 1:CAS:528:DC%2BD2MXht1ShtrnO 16199517 1239896
