{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:51:50Z","timestamp":1787003510666,"version":"build-2736575974"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T00:00:00Z","timestamp":1680566400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T00:00:00Z","timestamp":1680566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DK048351"],"award-info":[{"award-number":["R01 DK048351"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["ULTR001881\/DK041301"],"award-info":[{"award-number":["ULTR001881\/DK041301"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions may contribute to obesity pathogenesis. In this study, we use a machine learning approach to leverage the enormous amount of microstructural neuroimaging and fecal metabolomic data to better understand key drivers of the obese compared to overweight phenotype. Our findings reveal that although gut-derived factors play a role in this distinction, it is primarily brain-directed changes that differentiate obese from overweight individuals. Of the key gut metabolites that emerged from our model, many are likely at least in part derived or influenced by the gut-microbiota, including some amino-acid derivatives. Remarkably, key regions outside of the central nervous system extended reward network emerged as important differentiators, suggesting a role for previously unexplored neural pathways in the pathogenesis of obesity.<\/jats:p>","DOI":"10.1038\/s41598-023-32713-2","type":"journal-article","created":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T07:12:19Z","timestamp":1680592339000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Machine learning model to predict obesity using gut metabolite and brain microstructure data"],"prefix":"10.1038","volume":"13","author":[{"given":"Vadim","family":"Osadchiy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshan","family":"Bal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeran A.","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama","family":"Kunapuli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0105-8063","authenticated-orcid":false,"given":"Tien","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priten","family":"Vora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Petrasek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Stains","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1669-9624","authenticated-orcid":false,"given":"Arpana","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,4,4]]},"reference":[{"key":"32713_CR1","unstructured":"CDC, C. f. D. C. a. P. Overweight and Obesity. http:\/\/www.cdc.gov\/obesity\/data\/adult.html (2014)."},{"key":"32713_CR2","unstructured":"http:\/\/www.who.int\/mediacentre\/factsheets\/fs311\/en\/. Obesity and Overweight. Fact Sheet (2016)."},{"key":"32713_CR3","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1038\/ijo.2010.222","volume":"35","author":"JJ Reilly","year":"2011","unstructured":"Reilly, J. J. & Kelly, J. Long-term impact of overweight and obesity in childhood and adolescence on morbidity and premature mortality in adulthood: Systematic review. Int. J. Obes. (Lond.) 35, 891\u2013898. https:\/\/doi.org\/10.1038\/ijo.2010.222 (2011).","journal-title":"Int. J. Obes. (Lond.)"},{"key":"32713_CR4","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1016\/j.clnu.2018.07.021","volume":"38","author":"M Jiang","year":"2019","unstructured":"Jiang, M. et al. Dose-response relationship between body mass index and risks of all-cause mortality and disability among the elderly: A systematic review and meta-analysis. Clin. Nutr. 38, 1511\u20131523. https:\/\/doi.org\/10.1016\/j.clnu.2018.07.021 (2019).","journal-title":"Clin. Nutr."},{"key":"32713_CR5","doi-asserted-by":"publisher","first-page":"4228","DOI":"10.1038\/s41598-018-22551-y","volume":"8","author":"J Yu","year":"2018","unstructured":"Yu, J. et al. The dose-response analysis between BMI and common chronic diseases in northeast China. Sci. Rep. 8, 4228. https:\/\/doi.org\/10.1038\/s41598-018-22551-y (2018).","journal-title":"Sci. Rep."},{"key":"32713_CR6","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1210\/er.2017-00111","volume":"38","author":"MW Schwartz","year":"2017","unstructured":"Schwartz, M. W. et al. Obesity pathogenesis: An endocrine society scientific statement. Endocr. Rev. 38, 267\u2013296. https:\/\/doi.org\/10.1210\/er.2017-00111 (2017).","journal-title":"Endocr. Rev."},{"key":"32713_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-0341-5","author":"A Gupta","year":"2020","unstructured":"Gupta, A., Osadchiy, V. & Mayer, E. A. Brain-gut-microbiome interactions in obesity and food addiction. Nat. Rev. Gastroenterol. Hepatol. https:\/\/doi.org\/10.1038\/s41575-020-0341-5 (2020).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"32713_CR8","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1038\/35051587","volume":"409","author":"M Nakazato","year":"2001","unstructured":"Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194\u2013198. https:\/\/doi.org\/10.1038\/35051587 (2001).","journal-title":"Nature"},{"key":"32713_CR9","doi-asserted-by":"publisher","first-page":"2540","DOI":"10.2337\/diabetes.50.11.2540","volume":"50","author":"AM Wren","year":"2001","unstructured":"Wren, A. M. et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes 50, 2540\u20132547. https:\/\/doi.org\/10.2337\/diabetes.50.11.2540 (2001).","journal-title":"Diabetes"},{"key":"32713_CR10","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s11154-014-9289-5","volume":"15","author":"M Shah","year":"2014","unstructured":"Shah, M. & Vella, A. Effects of GLP-1 on appetite and weight. Rev. Endocr. Metab. Disord. 15, 181\u2013187. https:\/\/doi.org\/10.1007\/s11154-014-9289-5 (2014).","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"32713_CR11","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1113\/jphysiol.2008.164269","volume":"587","author":"E Karra","year":"2009","unstructured":"Karra, E., Chandarana, K. & Batterham, R. L. The role of peptide YY in appetite regulation and obesity. J. Physiol. 587, 19\u201325. https:\/\/doi.org\/10.1113\/jphysiol.2008.164269 (2009).","journal-title":"J. Physiol."},{"key":"32713_CR12","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1016\/j.cell.2015.02.047","volume":"161","author":"JM Yano","year":"2015","unstructured":"Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264\u2013276. https:\/\/doi.org\/10.1016\/j.cell.2015.02.047 (2015).","journal-title":"Cell"},{"key":"32713_CR13","doi-asserted-by":"publisher","first-page":"1052","DOI":"10.1002\/hbm.21268","volume":"33","author":"S Kullmann","year":"2012","unstructured":"Kullmann, S. et al. The obese brain: Association of body mass index and insulin sensitivity with resting state network functional connectivity. Hum. Brain Mapp. 33, 1052\u20131061. https:\/\/doi.org\/10.1002\/hbm.21268 (2012).","journal-title":"Hum. Brain Mapp."},{"key":"32713_CR14","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1002\/hbm.20870","volume":"31","author":"CA Raji","year":"2010","unstructured":"Raji, C. A. et al. Brain structure and obesity. Hum. Brain Mapp. 31, 353\u2013364. https:\/\/doi.org\/10.1002\/hbm.20870 (2010).","journal-title":"Hum. Brain Mapp."},{"key":"32713_CR15","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1111\/nmo.12125","volume":"25","author":"L Connolly","year":"2013","unstructured":"Connolly, L. et al. Differences in brain responses between lean and obese women to a sweetened drink. Neurogastroenterol. Motil. 25, 579-e460. https:\/\/doi.org\/10.1111\/nmo.12125 (2013).","journal-title":"Neurogastroenterol. Motil."},{"key":"32713_CR16","doi-asserted-by":"publisher","first-page":"2786","DOI":"10.1002\/hbm.22104","volume":"34","author":"I Garcia-Garcia","year":"2013","unstructured":"Garcia-Garcia, I. et al. Alterations of the salience network in obesity: A resting-state fMRI study. Hum. Brain Mapp. 34, 2786\u20132797. https:\/\/doi.org\/10.1002\/hbm.22104 (2013).","journal-title":"Hum. Brain Mapp."},{"key":"32713_CR17","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1053\/j.gastro.2014.01.023","volume":"146","author":"LA Kilpatrick","year":"2014","unstructured":"Kilpatrick, L. A. et al. Influence of sucrose ingestion on brainstem and hypothalamic intrinsic oscillations in lean and obese women. Gastroenterology 146, 1212\u20131221. https:\/\/doi.org\/10.1053\/j.gastro.2014.01.023 (2014).","journal-title":"Gastroenterology"},{"key":"32713_CR18","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1093\/brain\/awu132","volume":"137","author":"NA Crossley","year":"2014","unstructured":"Crossley, N. A. et al. The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain 137, 2382\u20132395. https:\/\/doi.org\/10.1093\/brain\/awu132 (2014).","journal-title":"Brain"},{"key":"32713_CR19","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1016\/j.neuroimage.2011.08.085","volume":"62","author":"O Sporns","year":"2012","unstructured":"Sporns, O. From simple graphs to the connectome: Networks in neuroimaging. Neuroimage 62, 881\u2013886. https:\/\/doi.org\/10.1016\/j.neuroimage.2011.08.085 (2012).","journal-title":"Neuroimage"},{"key":"32713_CR20","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1038\/nrn2575","volume":"10","author":"E Bullmore","year":"2009","unstructured":"Bullmore, E. & Sporns, O. Complex brain networks: Graph theoretical analysis of structural and functional systems. Nat. Rev. Neurosci. 10, 186\u2013198. https:\/\/doi.org\/10.1038\/nrn2575 (2009).","journal-title":"Nat. Rev. Neurosci."},{"key":"32713_CR21","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1016\/j.neuroimage.2012.01.107","volume":"60","author":"A Irimia","year":"2012","unstructured":"Irimia, A., Chambers, M. C., Torgerson, C. M. & Van Horn, J. D. Circular representation of human cortical networks for subject and population-level connectomic visualization. Neuroimage 60, 1340\u20131351. https:\/\/doi.org\/10.1016\/j.neuroimage.2012.01.107 (2012).","journal-title":"Neuroimage"},{"key":"32713_CR22","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1016\/j.neuroimage.2009.10.003","volume":"52","author":"M Rubinov","year":"2010","unstructured":"Rubinov, M. & Sporns, O. Complex network measures of brain connectivity: Uses and interpretations. Neuroimage 52, 1059\u20131069. https:\/\/doi.org\/10.1016\/j.neuroimage.2009.10.003 (2010).","journal-title":"Neuroimage"},{"key":"32713_CR23","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.nicl.2015.01.005","volume":"7","author":"A Gupta","year":"2015","unstructured":"Gupta, A. et al. Patterns of brain structural connectivity differentiate normal weight from overweight subjects. Neuroimage Clin. 7, 506\u2013517. https:\/\/doi.org\/10.1016\/j.nicl.2015.01.005 (2015).","journal-title":"Neuroimage Clin."},{"key":"32713_CR24","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1002\/osp4.362","volume":"5","author":"V Osadchiy","year":"2019","unstructured":"Osadchiy, V. et al. History of early life adversity is associated with increased food addiction and sex-specific alterations in reward network connectivity in obesity. Obes. Sci. Pract. 5, 416\u2013436. https:\/\/doi.org\/10.1002\/osp4.362 (2019).","journal-title":"Obes. Sci. Pract."},{"key":"32713_CR25","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.cgh.2018.10.002","volume":"17","author":"V Osadchiy","year":"2019","unstructured":"Osadchiy, V., Martin, C. R. & Mayer, E. A. The gut-brain axis and the microbiome: Mechanisms and clinical implications. Clin. Gastroenterol. Hepatol. 17, 322\u2013332. https:\/\/doi.org\/10.1016\/j.cgh.2018.10.002 (2019).","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"32713_CR26","doi-asserted-by":"publisher","first-page":"e0201772","DOI":"10.1371\/journal.pone.0201772","volume":"13","author":"V Osadchiy","year":"2018","unstructured":"Osadchiy, V. et al. Correlation of tryptophan metabolites with connectivity of extended central reward network in healthy subjects. PLoS ONE 13, e0201772. https:\/\/doi.org\/10.1371\/journal.pone.0201772 (2018).","journal-title":"PLoS ONE"},{"key":"32713_CR27","doi-asserted-by":"publisher","first-page":"5153","DOI":"10.3390\/nu6115153","volume":"6","author":"Y Zhang","year":"2014","unstructured":"Zhang, Y. et al. Obesity: Pathophysiology and intervention. Nutrients 6, 5153\u20135183. https:\/\/doi.org\/10.3390\/nu6115153 (2014).","journal-title":"Nutrients"},{"key":"32713_CR28","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1056\/NEJMra1514009","volume":"376","author":"SB Heymsfield","year":"2017","unstructured":"Heymsfield, S. B. & Wadden, T. A. Mechanisms, pathophysiology, and management of obesity. N. Engl. J. Med. 376, 254\u2013266. https:\/\/doi.org\/10.1056\/NEJMra1514009 (2017).","journal-title":"N. Engl. J. Med."},{"key":"32713_CR29","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/S0896-6273(02)00569-X","volume":"33","author":"B Fischl","year":"2002","unstructured":"Fischl, B. et al. Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron 33, 341\u2013355. https:\/\/doi.org\/10.1016\/S0896-6273(02)00569-X (2002).","journal-title":"Neuron"},{"key":"32713_CR30","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1006\/Nimg.1998.0395","volume":"9","author":"AM Dale","year":"1999","unstructured":"Dale, A. M., Fischl, B. & Sereno, M. I. Cortical surface-based analysis\u2014I. Segmentation and surface reconstruction. Neuroimage 9, 179\u2013194. https:\/\/doi.org\/10.1006\/Nimg.1998.0395 (1999).","journal-title":"Neuroimage"},{"key":"32713_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/J.Neuroimage.2010.06.010","volume":"53","author":"C Destrieux","year":"2010","unstructured":"Destrieux, C., Fischl, B., Dale, A. & Halgren, E. Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature. Neuroimage 53, 1\u201315. https:\/\/doi.org\/10.1016\/J.Neuroimage.2010.06.010 (2010).","journal-title":"Neuroimage"},{"key":"32713_CR32","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/j.neuroimage.2012.10.066","volume":"66C","author":"A Irimia","year":"2012","unstructured":"Irimia, A. & Van Horn, J. D. The structural, connectomic and network covariance of the human brain. Neuroimage 66C, 489\u2013499. https:\/\/doi.org\/10.1016\/j.neuroimage.2012.10.066 (2012).","journal-title":"Neuroimage"},{"key":"32713_CR33","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.neuroimage.2010.12.053","volume":"55","author":"MC Chiang","year":"2011","unstructured":"Chiang, M. C. et al. BDNF gene effects on brain circuitry replicated in 455 twins. Neuroimage 55, 448\u2013454. https:\/\/doi.org\/10.1016\/j.neuroimage.2010.12.053 (2011).","journal-title":"Neuroimage"},{"key":"32713_CR34","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1161\/01.CIR.99.12.1611","volume":"99","author":"Y Mori","year":"1999","unstructured":"Mori, Y. et al. Three-dimensional reconstruction of the color Doppler-imaged vena contracta for quantifying aortic regurgitation: Studies in a chronic animal model. Circulation 99, 1611\u20131617 (1999).","journal-title":"Circulation"},{"key":"32713_CR35","doi-asserted-by":"publisher","first-page":"247","DOI":"10.31887\/DCNS.2013.15.3\/osporns","volume":"15","author":"O Sporns","year":"2013","unstructured":"Sporns, O. Structure and function of complex brain networks. Dialog. Clin. Neurosci. 15, 247\u2013262 (2013).","journal-title":"Dialog. Clin. Neurosci."},{"key":"32713_CR36","doi-asserted-by":"publisher","first-page":"168702","DOI":"10.1103\/PhysRevLett.101.168702","volume":"101","author":"T Opsahl","year":"2008","unstructured":"Opsahl, T., Colizza, V., Panzarasa, P. & Ramasco, J. J. Prominence and control: The weighted rich-club effect. Phys. Rev. Lett. 101, 168702. https:\/\/doi.org\/10.1103\/PhysRevLett.101.168702 (2008).","journal-title":"Phys. Rev. Lett."},{"key":"32713_CR37","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.socnet.2010.03.006","volume":"32","author":"T Opsahl","year":"2010","unstructured":"Opsahl, T., Agneessens, F. & Skortez, J. Node centrality in weighted networks: Generalizing degree and shortest paths. Soc. Netw. 32, 245\u2013251 (2010).","journal-title":"Soc. Netw."},{"key":"32713_CR38","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s40337-022-00534-9","volume":"10","author":"A Gupta","year":"2022","unstructured":"Gupta, A. et al. Complex functional brain network properties in anorexia nervosa. J. Eat Disord. 10, 13. https:\/\/doi.org\/10.1186\/s40337-022-00534-9 (2022).","journal-title":"J. Eat Disord."},{"key":"32713_CR39","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1038\/ijo.2017.86","volume":"41","author":"A Gupta","year":"2017","unstructured":"Gupta, A. et al. Sex differences in the influence of body mass index on anatomical architecture of brain networks. Int. J. Obes. (Lond.) 41, 1185\u20131195. https:\/\/doi.org\/10.1038\/ijo.2017.86 (2017).","journal-title":"Int. J. Obes. (Lond.)"},{"key":"32713_CR40","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1002\/oby.22870","volume":"28","author":"TS Dong","year":"2020","unstructured":"Dong, T. S. et al. A distinct brain-gut-microbiome profile exists for females with obesity and food addiction. Obes. (Silver Spring) 28, 1477\u20131486. https:\/\/doi.org\/10.1002\/oby.22870 (2020).","journal-title":"Obes. (Silver Spring)"},{"key":"32713_CR41","first-page":"576","volume":"9","author":"X Qui","year":"2014","unstructured":"Qui, X., Fu, D. & Fu, Z. An efficient dimensionality reduction approach for small-sample size and high-dimensional data modeling. J. Comput. 9, 576\u2013580 (2014).","journal-title":"J. Comput."},{"key":"32713_CR42","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.1016\/j.patcog.2015.03.009","volume":"48","author":"T Wong","year":"2016","unstructured":"Wong, T. Performance evaluation of classification algorithms by k-fold and leave-one-out cross validation. Pattern Recogn. 48, 2839\u20132846. https:\/\/doi.org\/10.1016\/j.patcog.2015.03.009 (2016).","journal-title":"Pattern Recogn."},{"key":"32713_CR43","doi-asserted-by":"publisher","first-page":"253","DOI":"10.3390\/genes9060301","volume":"9","author":"Q Chen","year":"2018","unstructured":"Chen, Q., Meng, Z., Liu, X., Jin, Q. & Su, R. Decision variants for the automatic determination of optimal feature subset in RF-RFE. Genes Basel 9, 253. https:\/\/doi.org\/10.3390\/genes9060301 (2018).","journal-title":"Genes Basel"},{"key":"32713_CR44","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1007\/978-3-540-45087-0_28","volume":"18","author":"P Golland","year":"2003","unstructured":"Golland, P. & Fischl, B. Permutation tests for classification: Towards statistical significance in image-based studies. Inf. Process Med. Imaging 18, 330\u2013341. https:\/\/doi.org\/10.1007\/978-3-540-45087-0_28 (2003).","journal-title":"Inf. Process Med. Imaging"},{"key":"32713_CR45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1196\/annals.1440.011","volume":"1124","author":"RL Buckner","year":"2008","unstructured":"Buckner, R. L., Andrews-Hanna, J. R. & Schacter, D. L. The brain\u2019s default network: Anatomy, function, and relevance to disease. Ann. N. Y. Acad. Sci. 1124, 1\u201338. https:\/\/doi.org\/10.1196\/annals.1440.011 (2008).","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"32713_CR46","doi-asserted-by":"publisher","first-page":"12729","DOI":"10.1523\/JNEUROSCI.4366-09.2009","volume":"29","author":"ME Raichle","year":"2009","unstructured":"Raichle, M. E. A paradigm shift in functional brain imaging. J. Neurosci. 29, 12729\u201312734. https:\/\/doi.org\/10.1523\/JNEUROSCI.4366-09.2009 (2009).","journal-title":"J. Neurosci."},{"key":"32713_CR47","doi-asserted-by":"publisher","first-page":"2316","DOI":"10.1038\/oby.2011.119","volume":"19","author":"JR Tregellas","year":"2011","unstructured":"Tregellas, J. R. et al. Altered default network activity in obesity. Obes. (Silver Spring) 19, 2316\u20132321. https:\/\/doi.org\/10.1038\/oby.2011.119 (2011).","journal-title":"Obes. (Silver Spring)"},{"key":"32713_CR48","doi-asserted-by":"publisher","first-page":"234","DOI":"10.3803\/EnM.2019.34.3.234","volume":"34","author":"MAB Siddik","year":"2019","unstructured":"Siddik, M. A. B. & Shin, A. C. Recent progress on branched-chain amino acids in obesity, diabetes, and beyond. Endocrinol. Metab. (Seoul) 34, 234\u2013246. https:\/\/doi.org\/10.3803\/EnM.2019.34.3.234 (2019).","journal-title":"Endocrinol. Metab. (Seoul)"},{"key":"32713_CR49","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.cmet.2009.02.002","volume":"9","author":"CB Newgard","year":"2009","unstructured":"Newgard, C. B. et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 9, 311\u2013326. https:\/\/doi.org\/10.1016\/j.cmet.2009.02.002 (2009).","journal-title":"Cell Metab."},{"key":"32713_CR50","doi-asserted-by":"publisher","first-page":"1112","DOI":"10.1093\/ajcn\/77.5.1112","volume":"77","author":"L Breum","year":"2003","unstructured":"Breum, L., Rasmussen, M. H., Hilsted, J. & Fernstrom, J. D. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am. J. Clin. Nutr. 77, 1112\u20131118. https:\/\/doi.org\/10.1093\/ajcn\/77.5.1112 (2003).","journal-title":"Am. J. Clin. Nutr."},{"key":"32713_CR51","doi-asserted-by":"publisher","first-page":"319S","DOI":"10.1093\/jn\/136.1.319S","volume":"136","author":"DK Layman","year":"2006","unstructured":"Layman, D. K. & Walker, D. A. Potential importance of leucine in treatment of obesity and the metabolic syndrome. J. Nutr. 136, 319S-323S. https:\/\/doi.org\/10.1093\/jn\/136.1.319S (2006).","journal-title":"J. Nutr."},{"key":"32713_CR52","doi-asserted-by":"publisher","first-page":"1241214","DOI":"10.1126\/science.1241214","volume":"341","author":"VK Ridaura","year":"2013","unstructured":"Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214. https:\/\/doi.org\/10.1126\/science.1241214 (2013).","journal-title":"Science"},{"key":"32713_CR53","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.cell.2018.09.055","volume":"175","author":"A Koh","year":"2018","unstructured":"Koh, A. et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell 175, 947\u2013961. https:\/\/doi.org\/10.1016\/j.cell.2018.09.055 (2018).","journal-title":"Cell"},{"key":"32713_CR54","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.tem.2018.01.002","volume":"29","author":"AR Hamoud","year":"2018","unstructured":"Hamoud, A. R., Weaver, L., Stec, D. E. & Hinds, T. D. Jr. Bilirubin in the liver-gut signaling axis. Trends Endocrinol. Metab. 29, 140\u2013150. https:\/\/doi.org\/10.1016\/j.tem.2018.01.002 (2018).","journal-title":"Trends Endocrinol. Metab."},{"key":"32713_CR55","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1016\/j.drudis.2013.05.017","volume":"18","author":"JE Piletz","year":"2013","unstructured":"Piletz, J. E. et al. Agmatine: Clinical applications after 100 years in translation. Drug Discov. Today 18, 880\u2013893. https:\/\/doi.org\/10.1016\/j.drudis.2013.05.017 (2013).","journal-title":"Drug Discov. Today"},{"key":"32713_CR56","doi-asserted-by":"publisher","first-page":"885","DOI":"10.2165\/00023210-200721110-00002","volume":"21","author":"A Halaris","year":"2007","unstructured":"Halaris, A. & Plietz, J. Agmatine\u202f: Metabolic pathway and spectrum of activity in brain. CNS Drugs 21, 885\u2013900. https:\/\/doi.org\/10.2165\/00023210-200721110-00002 (2007).","journal-title":"CNS Drugs"},{"key":"32713_CR57","doi-asserted-by":"publisher","first-page":"900","DOI":"10.3389\/fphys.2018.00900","volume":"9","author":"ES Bliss","year":"2018","unstructured":"Bliss, E. S. & Whiteside, E. The gut-brain axis, the human gut microbiota and their integration in the development of obesity. Front. Physiol. 9, 900. https:\/\/doi.org\/10.3389\/fphys.2018.00900 (2018).","journal-title":"Front. Physiol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-32713-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-32713-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-32713-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,4]],"date-time":"2023-04-04T07:35:41Z","timestamp":1680593741000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-32713-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,4]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["32713"],"URL":"https:\/\/doi.org\/10.1038\/s41598-023-32713-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,4]]},"assertion":[{"value":"3 September 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 March 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 April 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5488"}}