{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:48:14Z","timestamp":1787662094065,"version":"build-2736575974"},"reference-count":37,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T00:00:00Z","timestamp":1701129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["209933838"],"award-info":[{"award-number":["209933838"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["82DZD00602"],"award-info":[{"award-number":["82DZD00602"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["201706170052"],"award-info":[{"award-number":["201706170052"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Deutsches Zentrum f\u00fcr Diabetesforschung","award":["209933838"],"award-info":[{"award-number":["209933838"]}]},{"name":"Deutsches Zentrum f\u00fcr Diabetesforschung","award":["82DZD00602"],"award-info":[{"award-number":["82DZD00602"]}]},{"name":"Deutsches Zentrum f\u00fcr Diabetesforschung","award":["201706170052"],"award-info":[{"award-number":["201706170052"]}]},{"name":"China Scholarship Council","award":["209933838"],"award-info":[{"award-number":["209933838"]}]},{"name":"China Scholarship Council","award":["82DZD00602"],"award-info":[{"award-number":["82DZD00602"]}]},{"name":"China Scholarship Council","award":["201706170052"],"award-info":[{"award-number":["201706170052"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In previous genome-wide association studies (GWAS), genetic loci associated with obesity and impaired fat distribution (FD) have been identified. In the present study, we elucidated the role of the PEMT gene, including the waist\u2013hip-ratio-associated single nucleotide polymorphism rs4646404, and its influence on obesity-related metabolic traits. DNA from 2926 metabolically well-characterized subjects was used for genotyping. PEMT expression was analyzed in paired visceral (vis) and subcutaneous (sc) adipose tissue (AT) from a subset of 574 individuals. Additionally, PEMT expression was examined in vis, sc AT and liver tissue in a separate cohort of 64 patients with morbid obesity and liver disease. An in vitro Pemt knockdown was conducted in murine epididymal and inguinal adipocytes. Our findings highlight tissue-specific variations in PEMT mRNA expression across the three studied tissues. Specifically, vis PEMT mRNA levels correlated significantly with T2D and were implicated in the progression of non-alcoholic steatohepatitis (NASH), in contrast to liver tissue, where no significant associations were found. Moreover, sc PEMT expression showed significant correlations with several anthropometric- and metabolic-related parameters. The rs4646404 was associated with vis AT PEMT expression and also with diabetes-related traits. Our in vitro experiments supported the influence of PEMT on adipogenesis, emphasizing its role in AT biology. In summary, our data suggest that PEMT plays a role in regulating FD and has implications in metabolic diseases.<\/jats:p>","DOI":"10.3390\/ijms242316850","type":"journal-article","created":{"date-parts":[[2023,11,28]],"date-time":"2023-11-28T06:45:35Z","timestamp":1701153935000},"page":"16850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The Role of Phosphatidylethanolamine N-Methyltransferase (PEMT) and Its Waist-Hip-Ratio-Associated Locus rs4646404 in Obesity-Related Metabolic Traits and Liver Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"Chang","family":"Sun","sequence":"first","affiliation":[{"name":"Medical Department III\u2014Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8994-0431","authenticated-orcid":false,"given":"David J. F.","family":"Holstein","sequence":"additional","affiliation":[{"name":"Medical Department III\u2014Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Garcia-Cubero","sequence":"additional","affiliation":[{"name":"Medical Department III\u2014Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5936-0217","authenticated-orcid":false,"given":"Yusef","family":"Moulla","sequence":"additional","affiliation":[{"name":"Clinic for Visceral, Transplantation and Thorax and Vascular Surgery, University Hospital Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Stroh","sequence":"additional","affiliation":[{"name":"Department of General, Abdominal and Pediatric Surgery, Municipal Hospital, 07548 Gera, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Clinic for Visceral, Transplantation and Thorax and Vascular Surgery, University Hospital Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Sch\u00f6n","sequence":"additional","affiliation":[{"name":"St\u00e4dtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, 76133 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"G\u00e4rtner","sequence":"additional","affiliation":[{"name":"St\u00e4dtisches Klinikum Karlsruhe, Clinic of Visceral Surgery, 76133 Karlsruhe, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Lohmann","sequence":"additional","affiliation":[{"name":"Municipal Clinic Dresden-Neustadt, 01129 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Dressler","sequence":"additional","affiliation":[{"name":"Municipal Clinic Dresden-Neustadt, 01129 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Stumvoll","sequence":"additional","affiliation":[{"name":"Medical Department III\u2014Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany"},{"name":"Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum M\u00fcnchen at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0208-2065","authenticated-orcid":false,"given":"Matthias","family":"Bl\u00fcher","sequence":"additional","affiliation":[{"name":"Medical Department III\u2014Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany"},{"name":"Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum M\u00fcnchen at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-5423","authenticated-orcid":false,"given":"Peter","family":"Kovacs","sequence":"additional","affiliation":[{"name":"Medical Department III\u2014Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9204-5780","authenticated-orcid":false,"given":"Esther","family":"Guiu-Jurado","sequence":"additional","affiliation":[{"name":"Medical Department III\u2014Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany"},{"name":"Deutsches Zentrum f\u00fcr Diabetesforschung e.V., 85764 Neuherberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1056\/NEJMra1514009","article-title":"Mechanisms, Pathophysiology, and Management of Obesity","volume":"376","author":"Heymsfield","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1055\/s-0029-1192044","article-title":"Adipose Tissue Dysfunction in Obesity","volume":"117","year":"2009","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/s41588-018-0183-z","article-title":"Genome-Wide Polygenic Scores for Common Diseases Identify Individuals with Risk Equivalent to Monogenic Mutations","volume":"50","author":"Khera","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.cell.2019.03.028","article-title":"Polygenic Prediction of Weight and Obesity Trajectories from Birth to Adulthood","volume":"177","author":"Khera","year":"2019","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.3389\/fgene.2020.575049","article-title":"Genetics of Obesity in East Asians","volume":"11","author":"Sun","year":"2020","journal-title":"Front. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sun, C., Kovacs, P., and Guiu-Jurado, E. (2021). Genetics of Body Fat Distribution: Comparative Analyses in Populations with European, Asian and African Ancestries. Genes, 12.","DOI":"10.3390\/genes12060841"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/nature14132","article-title":"New Genetic Loci Link Adipose and Insulin Biology to Body Fat Distribution","volume":"518","author":"Shungin","year":"2015","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1016\/j.bbalip.2012.07.017","article-title":"Physiological Roles of Phosphatidylethanolamine N-Methyltransferase","volume":"1831","author":"Vance","year":"2013","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.cmet.2006.03.007","article-title":"The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis","volume":"3","author":"Li","year":"2006","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1002\/hep.21763","article-title":"A Lipidomic Analysis of Nonalcoholic Fatty Liver Disease","volume":"46","author":"Puri","year":"2007","journal-title":"Hepatology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Piras, I.S., Raju, A., Don, J., Schork, N.J., Gerhard, G.S., and DiStefano, J.K. (2022). Hepatic PEMT Expression Decreases with Increasing NAFLD Severity. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23169296"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"22403","DOI":"10.1074\/jbc.M110.108514","article-title":"Impaired de Novo Choline Synthesis Explains Why Phosphatidylethanolamine N-Methyltransferase-Deficient Mice Are Protected from Diet-Induced Obesity","volume":"285","author":"Jacobs","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10986","DOI":"10.1096\/fj.201900679R","article-title":"Hepatic PEMT Activity Mediates Liver Health, Weight Gain, and Insulin Resistance","volume":"33","author":"Wan","year":"2019","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Sharma, N.K., Langberg, K.A., Mondal, A.K., and Das, S.K. (2013). Phospholipid Biosynthesis Genes and Susceptibility to Obesity: Analysis of Expression and Polymorphisms. PLoS ONE, 8.","DOI":"10.1371\/annotation\/7b3edc45-39c7-416b-a7dc-124f4846303d"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Presa, N., Dominguez-Herrera, A., van der Veen, J.N., Vance, D.E., and G\u00f3mez-Mu\u00f1oz, A. (2020). Implication of Phosphatidylethanolamine N-Methyltransferase in Adipocyte Differentiation. Biochim. Biophys. Acta Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2020.165853"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17338","DOI":"10.1074\/jbc.M111.234534","article-title":"Sequential Synthesis and Methylation of Phosphatidylethanolamine Promote Lipid Droplet Biosynthesis and Stability in Tissue Culture and in Vivo","volume":"286","author":"Wagner","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bbamem.2017.04.006","article-title":"The Critical Role of Phosphatidylcholine and Phosphatidylethanolamine Metabolism in Health and Disease","volume":"1859","author":"Kennelly","year":"2017","journal-title":"Biochim. Biophys. Acta BBA-Biomembr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11880","DOI":"10.1074\/jbc.M110.109843","article-title":"A Role for Sp1 in Transcriptional Regulation of Phosphatidylethanolamine N-Methyltransferase in Liver and 3T3-L1 Adipocytes","volume":"285","author":"Cole","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.cell.2011.09.045","article-title":"A Conserved SREBP-1\/Phosphatidylcholine Feedback Circuit Regulates Lipogenesis in Metazoans","volume":"147","author":"Walker","year":"2011","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/nature09968","article-title":"Aberrant Lipid Metabolism Disrupts Calcium Homeostasis Causing Liver Endoplasmic Reticulum Stress in Obesity","volume":"473","author":"Fu","year":"2011","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1002\/hep.26399","article-title":"Excess S-Adenosylmethionine Reroutes Phosphatidylethanolamine towards Phosphatidylcholine and Triglyceride Synthesis","volume":"58","author":"Cano","year":"2013","journal-title":"Hepatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1002\/hep.26499","article-title":"Finding the Balance: The Role of S-Adenosylmethionine and Phosphatidylcholine Metabolism in Development of Nonalcoholic Fatty Liver Disease","volume":"58","author":"Jacobs","year":"2013","journal-title":"Hepatology"},{"key":"ref_23","first-page":"1","article-title":"Cooperation of Liver Cells in Health and Disease","volume":"161","author":"Kmiec","year":"2001","journal-title":"Adv. Anat. Embryol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.4049\/jimmunol.143.5.1663","article-title":"Effect of Membrane Phospholipids on Activation of the Alternative Complement Pathway","volume":"143","author":"Mold","year":"1989","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14977","DOI":"10.1038\/ncomms14977","article-title":"Genome-Wide Meta-Analysis of 241,258 Adults Accounting for Smoking Behaviour Identifies Novel Loci for Obesity Traits","volume":"8","author":"Justice","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Winkler, T.W., Justice, A.E., Graff, M., Barata, L., Feitosa, M.F., Chu, S., Czajkowski, J., Esko, T., Fall, T., and Kilpel\u00e4inen, T.O. (2015). The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005378"},{"key":"ref_27","unstructured":"(2023, October 20). GTEx Portal. Available online: https:\/\/gtexportal.org\/home\/snp\/rs4646404."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/ng.840","article-title":"Principles for the Post-GWAS Functional Characterization of Cancer Risk Loci","volume":"43","author":"Freedman","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1152\/ajpendo.00586.2009","article-title":"Insulin-Sensitive Obesity","volume":"299","author":"Fasshauer","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1007\/s00125-001-0723-3","article-title":"Relation between Glycaemic Control, Hyperinsulinaemia and Plasma Concentrations of Soluble Adhesion Molecules in Patients with Impaired Glucose Tolerance or Type II Diabetes","volume":"45","author":"Unger","year":"2002","journal-title":"Diabetologia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S81","DOI":"10.2337\/dc14-S081","article-title":"Diagnosis and Classification of Diabetes Mellitus","volume":"37","author":"Association","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2903","DOI":"10.1007\/s11695-022-06180-z","article-title":"Effectiveness and Tolerability of a Two-Week Hypocaloric Protein-Rich Diet Prior to Obesity Surgery with Two Different Diet Interventions: A Prospective Randomized Trial","volume":"32","author":"Lange","year":"2022","journal-title":"Obes. Surg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14841","DOI":"10.1038\/srep14841","article-title":"Extensive Weight Loss Reveals Distinct Gene Expression Changes in Human Subcutaneous and Visceral Adipose Tissue OPEN","volume":"5","author":"Mardinoglu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"6676","DOI":"10.1073\/pnas.0601752103","article-title":"Evidence for a Role of Developmental Genes in the Origin of Obesity and Body Fat Distribution","volume":"103","author":"Gesta","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"34795","DOI":"10.1074\/jbc.274.49.34795","article-title":"\u03923-Adrenergic Stimulation Differentially Inhibits Insulin Signaling and Decreases Insulin-Induced Glucose Uptake in Brown Adipocytes","volume":"274","author":"Klein","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"E315","DOI":"10.1152\/ajpendo.90486.2008","article-title":"Depot-Specific Adipocyte Cell Lines Reveal Differential Drug-Induced Responses of White Adipocytes\u2014Relevance for Partial Lipodystrophy","volume":"296","author":"Kovsan","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16850\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:32:09Z","timestamp":1760131929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16850"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,28]]},"references-count":37,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316850"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316850","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,28]]}}}