{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T07:10:10Z","timestamp":1784013010427,"version":"3.55.0"},"reference-count":87,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003339","name":"Consejo Superior de Investigaciones Cientificas","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003339","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The global rise in obesity is predominantly driven by energy dense foods consumption and sedentary lifestyles that contribute to a growing burden of metabolic and neuroinflammatory comorbidities. Obesity is linked to a chronic low-grade inflammatory profile, as well as to a localized neuroendocrine imbalance and inflammatory response in the brain, including regions regulating energy homeostasis, reward and motivational centers. Anti-obesity medications that reduce body weight are being extensively used across the world, and the specific cerebral mechanisms underlying its action are yet to be clarified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the cerebral and systemic effects inherent to obesity development and treatment with celastrol, an anti-obesity and anti-inflammatory agent, in a murine model of diet-induced obesity (DIO) using a multimodal approach. We characterized obesity progression and celastrol acute treatment by comparing body weight (BW), food intake, changes in brain microstructure by in vivo magnetic resonance imaging (MRI) and ex vivo by immunofluorescence (IF), investigated its metabolic rearrangements using\n                      <jats:sup>1<\/jats:sup>\n                      H high-resolution magic angle spinning spectroscopy and draw the hormonal profiles between DIO and control animals, with or without treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our findings indicate that obesity induces detectable neuroinflammation, evident through diffusion MRI alterations and increased glial activation, with quantifiable morphological changes. Treatment resulted in significant BW reduction, diffusion MRI signal changes, particularly in the hypothalamus, a decrease in glial activation, a regularization of cerebral osmolyte concentrations, decreased cellular proliferation and astrocytic metabolism markers, and anti-inflammatory cytokine changes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results support the role of celastrol as an anti-obesity treatment, with anti-inflammatory effects in the hypothalamus and associated cerebral metabolic rearrangements, and prove MRI techniques as valid tools to characterize its effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-026-01530-4","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T23:35:59Z","timestamp":1782862559000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acute anti-obesity treatment with celastrol reduces body weight, cerebral inflammation and metabolic imbalances in mice"],"prefix":"10.1186","volume":"32","author":[{"given":"Adriana","family":"Ferreiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Holgado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Gonz\u00e1lez-Alday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Gonz\u00e1lez-Soto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia M.","family":"Fernandez-Sevilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngeles","family":"Vicente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"L\u00f3pez-Larrubia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Lizarbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"issue":"1","key":"1530_CR1","doi-asserted-by":"publisher","first-page":"e23288","DOI":"10.1016\/j.heliyon.2023.e23288","volume":"10","author":"K Ahmed","year":"2024","unstructured":"Ahmed K, Choi HN, Park JS, Kim YG, Bae MK, Yim JE. Taurine supplementation alters gene expression profiles in white adipose tissue of obese C57BL\/6J mice: Inflammation and lipid synthesis perspectives. Heliyon England. 2024;10(1):e23288.","journal-title":"Heliyon England"},{"issue":"4","key":"1530_CR2","doi-asserted-by":"publisher","first-page":"908","DOI":"10.2337\/db16-0586","volume":"66","author":"C Andr\u00e9","year":"2016","unstructured":"Andr\u00e9 C, Guzman-Quevedo O, Rey C, R\u00e9mus-Borel J, Clark S, Castellanos-Jankiewicz A, et al. Inhibiting microglia expansion prevents diet-induced hypothalamic and peripheral inflammation. Diabetes. 2016;66(4):908\u201319.","journal-title":"Diabetes"},{"issue":"1","key":"1530_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v067.i01","volume":"67","author":"D Bates","year":"2015","unstructured":"Bates D, M\u00e4chler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67(1):1\u201348.","journal-title":"J Stat Softw"},{"issue":"8","key":"1530_CR4","doi-asserted-by":"publisher","first-page":"2858","DOI":"10.1210\/en.2014-1121","volume":"155","author":"KE Berkseth","year":"2014","unstructured":"Berkseth KE, Guyenet SJ, Melhorn SJ, Lee D, Thaler JP, Schur EA, et al. Hypothalamic gliosis associated with high-fat diet feeding is reversible in mice: a combined immunohistochemical and magnetic resonance imaging study. Endocrinol US. 2014;155(8):2858\u201367.","journal-title":"Endocrinol US"},{"key":"1530_CR5","doi-asserted-by":"crossref","unstructured":"Berridge KC. \u2018Liking\u2019 and \u2018wanting\u2019 food rewards: Brain substrates and roles in eating disorders. Physiol. Behav. 2009;97(5):537\u201350. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0031938409001206. Cited 2025 Feb 25","DOI":"10.1016\/j.physbeh.2009.02.044"},{"issue":"1","key":"1530_CR6","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1023\/A:1010933404324","volume":"45","author":"L Breiman","year":"2001","unstructured":"Breiman L. Random forests. Mach Learn. 2001;45(1):5\u201332.","journal-title":"Mach Learn"},{"issue":"151","key":"1530_CR7","doi-asserted-by":"publisher","first-page":"4745","DOI":"10.1210\/en.2010-0556","volume":"1","author":"D Briggs","year":"2010","unstructured":"Briggs D, Enriori P, Lemus M, Cowley M, Andrews Z. Diet-induced obesity causes ghrelin resistance in arcuate NPY\/AgRP neurons. Endocrinology. 2010;1(151):4745\u201355.","journal-title":"Endocrinology"},{"key":"1530_CR8","doi-asserted-by":"crossref","unstructured":"Buckman LB, Thompson MM, Lippert RN, Blackwell TS, Yull FE, Ellacott KLJ. Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. Mol. Metab. 2015;4(1):58\u201363. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2212877814001744. Cited 2025 Feb 25","DOI":"10.1016\/j.molmet.2014.10.001"},{"key":"1530_CR9","doi-asserted-by":"publisher","first-page":"1025108","DOI":"10.3389\/fnins.2022.1025108","volume":"16","author":"BW Campillo","year":"2022","unstructured":"Campillo BW, Galguera D, Cerdan S, L\u00f3pez-Larrubia P, Lizarbe B. Short-term high-fat diet alters the mouse brain magnetic resonance imaging parameters consistently with neuroinflammation on males and metabolic rearrangements on females. A pre-clinical study with an optimized selection of linear mixed-effects models. Front Neurosci. 2022;16:1025108.","journal-title":"Front Neurosci"},{"key":"1530_CR10","doi-asserted-by":"crossref","unstructured":"Cazettes F, Cohen JI, Yau PL, Talbot H, Convit A. Obesity-mediated inflammation may damage the brain circuit that regulates food intake. Brain Res. 2011.;1373;101\u20139. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S000689931002620X. Cited 2025 Feb 25","DOI":"10.1016\/j.brainres.2010.12.008"},{"key":"1530_CR11","doi-asserted-by":"crossref","unstructured":"Cheung MM, Hui ES, Chan KC, Helpern JA, Qi L, Wu EX. Does diffusion kurtosis imaging lead to better neural tissue characterization? A rodent brain maturation study. NeuroImage. 2009;45(2):386\u201392. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1053811908012767. Cited 2025 Feb 25","DOI":"10.1016\/j.neuroimage.2008.12.018"},{"issue":"5","key":"1530_CR12","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1049\/iet-ipr.2011.0161","volume":"6","author":"P Coup\u00e9","year":"2012","unstructured":"Coup\u00e9 P, Manj\u00f3n JV, Robles M, Collins DL. Adaptive multiresolution non-local means filter for three-dimensional magnetic resonance image denoising. IET Image Process Instit Engine Technol. 2012;6(5):558\u201368.","journal-title":"IET Image Process Instit Engine Technol"},{"key":"1530_CR13","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.neubiorev.2021.07.020","volume":"129","author":"J Daoust","year":"2021","unstructured":"Daoust J, Schaffer J, Zeighami Y, Dagher A, Garc\u00eda-Garc\u00eda I, Michaud A. White matter integrity differences in obesity: a meta-analysis of diffusion tensor imaging studies. Neurosci Biobehav Rev United States. 2021;129:133\u201341.","journal-title":"Neurosci Biobehav Rev United States"},{"key":"1530_CR14","doi-asserted-by":"publisher","unstructured":"De Moura E Dias M, Dos Reis SA, Da Concei\u00e7\u00e3o LL, Sediyama CMNDO, Pereira SS, De Oliveira LL, et al. Diet-induced obesity in animal models: points to consider and influence on metabolic markers. Diabetol. Metab. Syndr. 2021;13(1):32. Available from: https:\/\/dmsjournal.biomedcentral.com\/articles\/https:\/\/doi.org\/10.1186\/s13098-021-00647-2. Cited 2025 Feb 25","DOI":"10.1186\/s13098-021-00647-2"},{"issue":"5","key":"1530_CR15","doi-asserted-by":"publisher","first-page":"e70073","DOI":"10.1111\/jnc.70073","volume":"169","author":"R Dringen","year":"2025","unstructured":"Dringen R, Arend C. Glutathione metabolism of the brain-the role of astrocytes. J Neurochem England. 2025;169(5):e70073.","journal-title":"J Neurochem England"},{"issue":"2","key":"1530_CR16","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.neuroimage.2011.12.038","volume":"61","author":"JMN Duarte","year":"2012","unstructured":"Duarte JMN, Lei H, Mlyn\u00e1rik V, Gruetter R. The neurochemical profile quantified by in vivo 1H NMR spectroscopy. NeuroImage US. 2012;61(2):342\u201362.","journal-title":"NeuroImage US"},{"key":"1530_CR17","unstructured":"Fadnavis S, Batson J, Garyfallidis E. Patch2Self: denoising diffusion MRI with self-supervised learning. arXiv; 2020. Available from: http:\/\/arxiv.org\/abs\/2011.01355. Cited 2025 Jan 15"},{"issue":"4","key":"1530_CR18","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1038\/s41591-019-0358-x","volume":"25","author":"X Feng","year":"2019","unstructured":"Feng X, Guan D, Auen T, Choi JW, Salazar Hern\u00e1ndez MA, Lee J, et al. IL1R1 is required for celastrol\u2019s leptin-sensitization and antiobesity effects. Nat Med. 2019;25(4):575\u201382.","journal-title":"Nat Med"},{"key":"1530_CR19","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Sevilla LM, Valencia J, Ortiz-S\u00e1nchez P, Fraile-Ramos A, Zuluaga P, Jim\u00e9nez E, et al. High BMP4 expression in low\/intermediate risk BCP-ALL identifies children with poor outcomes. Blood. 2022;139(22):3303\u201313. Available from: https:\/\/ashpublications.org\/blood\/article\/139\/22\/3303\/484443\/High-BMP4-expression-in-low-intermediate-risk-BCP. Cited 2025 Jan 30","DOI":"10.1182\/blood.2021013506"},{"key":"1530_CR20","doi-asserted-by":"publisher","unstructured":"Fern\u00e1ndez\u2010Sevilla LM, Valencia J, Flores\u2010Villalobos MA, Gonzalez\u2010Murillo \u00c1, Saced\u00f3n R, Jim\u00e9nez E, et al. The choroid plexus stroma constitutes a sanctuary for paediatric B \u2010cell precursor acute lymphoblastic leukaemia in the central nervous system. J Pathol. 2020;252(2):189\u2013200. https:\/\/doi.org\/10.1002\/path.5510. Cited 2025 Jan 30","DOI":"10.1002\/path.5510"},{"key":"1530_CR21","doi-asserted-by":"publisher","unstructured":"Ferrario CR, Labou\u00e8be G, Liu S, Nieh EH, Routh VH, Xu S, et al. Homeostasis meets motivation in the battle to control food intake. J Neurosci. 2016;36(45):11469\u201381. https:\/\/doi.org\/10.1523\/JNEUROSCI.2338-16.2016. Cited 2025 Feb 25","DOI":"10.1523\/JNEUROSCI.2338-16.2016"},{"issue":"1","key":"1530_CR22","doi-asserted-by":"publisher","first-page":"36801","DOI":"10.1038\/srep36801","volume":"6","author":"ALC Figueroa","year":"2016","unstructured":"Figueroa ALC, Figueiredo H, Rebuffat SA, Vieira E, Gomis R. Taurine treatment modulates circadian rhythms in mice fed a high fat diet. Sci Rep. 2016;6(1):36801.","journal-title":"Sci Rep"},{"issue":"12","key":"1530_CR23","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1038\/nm1295-1311","volume":"1","author":"RC Frederich","year":"1995","unstructured":"Frederich RC, Hamann A, Anderson S, L\u00f6llmann B, Lowell BB, Flier JS. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med US. 1995;1(12):1311\u20134.","journal-title":"Nat Med US"},{"issue":"1","key":"1530_CR24","doi-asserted-by":"publisher","first-page":"3611","DOI":"10.1038\/ncomms4611","volume":"5","author":"G Frost","year":"2014","unstructured":"Frost G, Sleeth ML, Sahuri-Arisoylu M, Lizarbe B, Cerdan S, Brody L, et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat Commun. 2014;5(1):3611.","journal-title":"Nat Commun"},{"key":"1530_CR25","doi-asserted-by":"crossref","unstructured":"Gao Y, Bielohuby M, Fleming T, Grabner GF, Foppen E, Bernhard W, et al. Dietary sugars, not lipids, drive hypothalamic inflammation. Mol Metab. 2017;6(8):897\u2013908. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2212877817302399. Cited 2025 Feb 25","DOI":"10.1016\/j.molmet.2017.06.008"},{"issue":"1","key":"1530_CR26","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41593-018-0286-y","volume":"22","author":"C Garc\u00eda-C\u00e1ceres","year":"2019","unstructured":"Garc\u00eda-C\u00e1ceres C, Balland E, Prevot V, Luquet S, Woods SC, Koch M, et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci. 2019;22(1):7\u201314.","journal-title":"Nat Neurosci"},{"key":"1530_CR27","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-C\u00e1ceres C, Balland E, Prevot V, Luquet S, Woods SC, Koch M, et al. Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat. Neurosci. 2019a;22(1):7\u201314. Available from: https:\/\/www.nature.com\/articles\/s41593-018-0286-y. Cited 2025 Feb 25","DOI":"10.1038\/s41593-018-0286-y"},{"key":"1530_CR28","doi-asserted-by":"crossref","unstructured":"Garcia-Hernandez R, Cerd\u00e1n Cerd\u00e1 A, Trouve Carpena A, Drakesmith M, Koller K, Jones DK, et al. Mapping microglia and astrocyte activation in vivo using diffusion MRI. Sci Adv Am Assoc Advance Sci. 2022;8(21):eabq2923.","DOI":"10.1126\/sciadv.abq2923"},{"issue":"11","key":"1530_CR29","doi-asserted-by":"publisher","first-page":"1090","DOI":"10.1080\/1028415X.2022.2131062","volume":"26","author":"AM Garcia-Serrano","year":"2023","unstructured":"Garcia-Serrano AM, Vieira Joao PP, Veronika F, Duarte JMN. Taurine and N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice. Nutr Neurosci Taylor & Francis. 2023;26(11):1090\u2013102.","journal-title":"Nutr Neurosci Taylor & Francis"},{"key":"1530_CR30","first-page":"8","volume":"8","author":"E Garyfallidis","year":"2014","unstructured":"Garyfallidis E, Brett M, Amirbekian B, Rokem A, van der Walt S, Descoteaux M, et al. Dipy, a library for the analysis of diffusion MRI data. Front Neuroinformatics Switzerland. 2014;8:8.","journal-title":"Front Neuroinformatics. Switzerland"},{"key":"1530_CR31","doi-asserted-by":"crossref","unstructured":"Gruber T, Pan C, Contreras RE, Wiedemann T, Morgan DA, Skowronski AA, et al. Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. Cell Metab. 2021;33(6):1155\u20131170.e10. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S155041312100173X. Cited 2025 Feb 25","DOI":"10.1016\/j.cmet.2021.04.007"},{"key":"1530_CR86","doi-asserted-by":"publisher","unstructured":"Guadilla I, Lizarbe B, Barrios L, Cerd\u00e1n S, L\u00f3pez-Larrubia P. Integrative analysis of physiological responses to high fat feeding with diffusion tensor images and neurochemical profiles of the mouse brain. Int J Obes. 2021;45:1203\u201314. https:\/\/doi.org\/10.1038\/s41366-021-00775-9.","DOI":"10.1038\/s41366-021-00775-9"},{"key":"1530_CR32","doi-asserted-by":"publisher","unstructured":"Gupta S, Knight AG, Gupta S, Keller JN, Bruce\u2010Keller AJ. Saturated long\u2010chain fatty acids activate inflammatory signaling in astrocytes. J. Neurochem. 2012;120(6):1060\u201371. https:\/\/doi.org\/10.1111\/j.1471-4159.2012.07660.x. Cited 2025 Feb 25","DOI":"10.1111\/j.1471-4159.2012.07660.x"},{"key":"1530_CR33","doi-asserted-by":"publisher","unstructured":"Horvath TL, Sarman B, Garc\u00eda-C\u00e1ceres C, Enriori PJ, Sotonyi P, Shanabrough M, et al. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. Proc. Natl. Acad. Sci. 2010;107(33):14875\u201380. https:\/\/doi.org\/10.1073\/pnas.1004282107. Cited 2025 Feb 25","DOI":"10.1073\/pnas.1004282107"},{"key":"1530_CR34","doi-asserted-by":"crossref","unstructured":"Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444(7121):860\u20137. Available from: https:\/\/www.nature.com\/articles\/nature05485. Cited 2025 Feb 25","DOI":"10.1038\/nature05485"},{"key":"1530_CR35","doi-asserted-by":"crossref","unstructured":"Iskusnykh IY, Zakharova AA, Pathak D. Glutathione in brain disorders and aging. Mol. Basel Switz. Switzerland; 2022;27(1).","DOI":"10.3390\/molecules27010324"},{"issue":"1","key":"1530_CR36","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1172\/JCI88878","volume":"127","author":"A Jais","year":"2017","unstructured":"Jais A, Br\u00fcning JC. Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest Am Soc Clin Invest. 2017;127(1):24\u201332.","journal-title":"J Clin Invest Am Soc Clin Invest"},{"issue":"1","key":"1530_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-63949-3","volume":"16","author":"M Kikhia","year":"2025","unstructured":"Kikhia M, Schilling S, Herzog M-L, Livne M, Semtner M, Tay TL, et al. Multicolor fate mapping of microglia reveals polyclonal proliferation, heterogeneity, and cell-cell interactions after ischemic stroke in mice. Nat Commun. 2025;16(1):8294.","journal-title":"Nat Commun"},{"issue":"4","key":"1530_CR38","first-page":"1","volume":"8","author":"JE Kim","year":"2013","unstructured":"Kim JE, Lee MH, Nam DH, Song HK, Kang YS, Lee JE, et al. Celastrol, an NF-\u03baB inhibitor, improves insulin resistance and attenuates renal injury in db\/db mice. PLOS ONE Public Libr Sci. 2013;8(4):1\u201311.","journal-title":"PLOS ONE Public Libr Sci"},{"issue":"1","key":"1530_CR39","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1017\/S002966512400747X","volume":"85","author":"M Lages","year":"2026","unstructured":"Lages M, Carmo-Silva S, Barros R, Guarino MP. Effects of time-restricted eating on body composition, biomarkers of metabolism, inflammation, circadian system and oxidative stress in overweight and obesity: an exploratory review. Proc Nutr Soc. 2026;85(1):13\u201322.","journal-title":"Proc Nutr Soc"},{"key":"1530_CR40","doi-asserted-by":"publisher","unstructured":"Le Bihan D. Apparent diffusion coefficient and beyond: what diffusion mr imaging can tell us about tissue structure. Radiology. 2013;268(2):318\u201322. https:\/\/doi.org\/10.1148\/radiol.13130420. Cited 2025 Feb 25","DOI":"10.1148\/radiol.13130420"},{"key":"1530_CR41","doi-asserted-by":"crossref","unstructured":"Lenth RV. emmeans: estimated marginal means, aka least-squares means. 2017. p. 1.10.6. Available from: https:\/\/CRAN.R-project.org\/package=emmeans. Cited 2025 Jan 30","DOI":"10.32614\/CRAN.package.emmeans"},{"key":"1530_CR42","first-page":"23","volume":"30","author":"A Liaw","year":"2001","unstructured":"Liaw A, Wiener M. Classification and regression by randomforest. Forest. 2001;30:23.","journal-title":"Forest"},{"issue":"5","key":"1530_CR43","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/j.cell.2015.05.011","volume":"161","author":"J Liu","year":"2015","unstructured":"Liu J, Lee J, Salazar Hernandez MA, Mazitschek R, Ozcan U. Treatment of obesity with celastrol. Cell. 2015;161(5):999\u20131011.","journal-title":"Cell"},{"issue":"11","key":"1530_CR44","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1177\/0271678X20941263","volume":"40","author":"B Lizarbe","year":"2020","unstructured":"Lizarbe B, Campillo B, Guadilla I, L\u00f3pez-Larrubia P, Cerd\u00e1n S. Magnetic resonance assessment of the cerebral alterations associated with obesity development. J Cereb Blood Flow Metab off J Int Soc Cereb Blood Flow Metab US. 2020a;40(11):2135\u201351.","journal-title":"J Cereb Blood Flow Metab off J Int Soc Cereb Blood Flow Metab US"},{"issue":"6","key":"1530_CR45","first-page":"1295","volume":"43","author":"B Lizarbe","year":"2019","unstructured":"Lizarbe B, Cherix A, Duarte JMN, Cardinaux J-R, Gruetter R. High-fat diet consumption alters energy metabolism in the mouse hypothalamus. Int J Obes England. 2019;43(6):1295\u2013304.","journal-title":"Int J Obes 2005 England"},{"key":"1530_CR87","doi-asserted-by":"publisher","unstructured":"Lizarbe B, Soares AF, Larsson S, Duarte JMN. Neurochemical modifications in the hippocampus, cortex and hypothalamus of mice exposed to long-term high-fat. Diet Front Neurosci. Switzerland; 2018;12:985. https:\/\/doi.org\/10.3389\/fnins.2018.00985.","DOI":"10.3389\/fnins.2018.00985"},{"issue":"4","key":"1530_CR46","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.cmet.2015.08.005","volume":"22","author":"X Ma","year":"2015","unstructured":"Ma X, Xu L, Alberobello AT, Gavrilova O, Bagattin A, Skarulis M, et al. Celastrol Protects against obesity and metabolic dysfunction through activation of a HSF1-PGC1\u03b1 transcriptional axis. Cell Metab Elsevier. 2015;22(4):695\u2013708.","journal-title":"Cell Metab Elsevier"},{"issue":"1","key":"1530_CR47","first-page":"139239","volume":"2013","author":"K Makki","year":"2013","unstructured":"Makki K, Froguel P, Wolowczuk I. Adipose tissue in obesity-related inflammation and insulin resistance: cells, cytokines, and chemokines. Int Sch Res Not John Wiley & Sons Ltd. 2013;2013(1):139239.","journal-title":"Int Sch Res Not John Wiley & Sons Ltd"},{"key":"1530_CR48","doi-asserted-by":"publisher","first-page":"150113","DOI":"10.1016\/j.brainres.2025.150113","volume":"1872","author":"TS Marinho","year":"2026","unstructured":"Marinho TS, Bittencourt JOA, Aguila MB, Mandarim-de-Lacerda CA. Tirzepatide reverses hypothalamic inflammation, cellular stress, and neuropeptide imbalance in metabolic\u2013menopausal dysfunction. Brain Res. 2026;1872:150113.","journal-title":"Brain Res"},{"issue":"11","key":"1530_CR49","doi-asserted-by":"publisher","first-page":"3011","DOI":"10.1016\/j.celrep.2019.02.044","volume":"26","author":"D Mishra","year":"2019","unstructured":"Mishra D, Richard JE, Maric I, Porteiro B, H\u00e4ring M, Kooijman S, et al. Parabrachial interleukin-6 reduces body weight and food intake and increases thermogenesis to regulate energy metabolism. Cell Rep US. 2019;26(11):3011-3026.e5.","journal-title":"Cell Rep US"},{"key":"1530_CR50","doi-asserted-by":"crossref","unstructured":"Nilsson C, Raun K, Yan F, Larsen MO, Tang-Christensen M. Laboratory animals as surrogate models of human obesity. Acta Pharmacol. Sin. 2012;33(2):173\u201381. Available from: https:\/\/www.nature.com\/articles\/aps2011203. Cited 2025 Feb 25","DOI":"10.1038\/aps.2011.203"},{"key":"1530_CR51","doi-asserted-by":"crossref","unstructured":"O\u2019Callaghan JP, Sriram K. Focused microwave irradiation of the brain preserves in vivo protein phosphorylation: comparison with other methods of sacrifice and analysis of multiple phosphoproteins. J Neurosci Methods 2004;135(1\u20132):159\u201368. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0165027003004321. Cited 2025 Jan 30","DOI":"10.1016\/j.jneumeth.2003.12.006"},{"key":"1530_CR52","doi-asserted-by":"crossref","unstructured":"O\u2019Connell MA, Belanger BA, Haaland PD. Calibration and assay development using the four-parameter logistic model. Chemom Intell Lab Syst 1993;20(2):97\u2013114. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/0169743993800086. Cited 2025 Feb 13","DOI":"10.1016\/0169-7439(93)80008-6"},{"issue":"4","key":"1530_CR53","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1002\/mrm.22708","volume":"65","author":"G Oz","year":"2011","unstructured":"Oz G, Tk\u00e1\u010d I. Short-echo, single-shot, full-intensity proton magnetic resonance spectroscopy for neurochemical profiling at 4 T: validation in the cerebellum and brainstem. Magn Reson Med US. 2011;65(4):901\u201310.","journal-title":"Magn Reson Med US"},{"issue":"11","key":"1530_CR54","doi-asserted-by":"publisher","first-page":"2456","DOI":"10.2337\/db18-0146","volume":"67","author":"K Pfuhlmann","year":"2018","unstructured":"Pfuhlmann K, Schriever SC, Baumann P, Kabra DG, Harrison L, Mazibuko-Mbeje SE, et al. Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1. Diabetes US. 2018;67(11):2456\u201365.","journal-title":"Diabetes US"},{"key":"1530_CR55","doi-asserted-by":"crossref","unstructured":"Plantera L, Bernhart SH, Immig K, Leyh J, Ceglarek U, Bechmann I. Diet-driven microglial activation: region-specific neuroinflammation in the mouse brain. Brain Sci. Switzerland; 2025;16(1).","DOI":"10.3390\/brainsci16010029"},{"key":"1530_CR56","doi-asserted-by":"publisher","unstructured":"Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, et al. Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol-Endocrinol Metab. 2009;296(5):E1003\u201312. https:\/\/doi.org\/10.1152\/ajpendo.90377.2008. Cited 2025 Feb 25","DOI":"10.1152\/ajpendo.90377.2008"},{"key":"1530_CR57","doi-asserted-by":"publisher","unstructured":"Provencher SW. Automatic quantitation of localized in vivo1 H spectra with LCModel. NMR Biomed. 2001;14(4):260\u20134. https:\/\/doi.org\/10.1002\/nbm.698. Cited 2025 Jan 30","DOI":"10.1002\/nbm.698"},{"key":"1530_CR58","unstructured":"R Core Team. R: A Language and environment for statistical computing. r foundation for statistical computing. Found Stat Comput Vienna Austria 2025; Available from: https:\/\/www.r-project.org\/"},{"key":"1530_CR59","unstructured":"R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. Found. Stat. Comput. Vienna Austria. 2021; Available from: https:\/\/www.r-project.org\/"},{"key":"1530_CR60","doi-asserted-by":"publisher","unstructured":"Ramalho AF, Bombassaro B, Dragano NR, Solon C, Morari J, Fioravante M, et al. Dietary fats promote functional and structural changes in the median eminence blood\/spinal fluid interface\u2014the protective role for BDNF. J. Neuroinflammation. 2018;15(1):10.https:\/\/doi.org\/10.1186\/s12974-017-1046-8. Cited 2025 Feb 25","DOI":"10.1186\/s12974-017-1046-8"},{"issue":"2","key":"1530_CR61","doi-asserted-by":"publisher","first-page":"100736","DOI":"10.1016\/j.jlr.2024.100736","volume":"66","author":"X Rong","year":"2025","unstructured":"Rong X, Wei F, Jiang Y, Ma Q, Wang D, Shen J. Microglial activation and hypothalamic structural plasticity in HFD obesity: insights from semaglutide and minocycline. J Lipid Res US. 2025;66(2):100736.","journal-title":"J Lipid Res US"},{"key":"1530_CR62","doi-asserted-by":"crossref","unstructured":"Rosenbaum JL, Melhorn SJ, Schoen S, Webb MF, De Leon MRB, Humphreys M, et al. Evidence that hypothalamic gliosis is related to impaired glucose homeostasis in adults with obesity. Diabetes Care. 2022;45(2):416\u201324. Available from: https:\/\/diabetesjournals.org\/care\/article\/45\/2\/416\/138998\/Evidence-That-Hypothalamic-Gliosis-Is-Related-to. Cited 2025 Feb 25","DOI":"10.2337\/dc21-1535"},{"key":"1530_CR63","doi-asserted-by":"crossref","unstructured":"Saito K, Davis KC, Morgan DA, Toth BA, Jiang J, Singh U, et al. Celastrol reduces obesity in MC4R deficiency and stimulates sympathetic nerve activity affecting metabolic and cardiovascular functions. Diabetes. 2019;68(6):1210\u201320. Available from: https:\/\/diabetesjournals.org\/diabetes\/article\/68\/6\/1210\/39729\/Celastrol-Reduces-Obesity-in-MC4R-Deficiency-and. Cited 2025 Feb 25","DOI":"10.2337\/db18-1167"},{"key":"1530_CR64","doi-asserted-by":"crossref","unstructured":"Saper CB, Chou TC, Elmquist JK. The need to feed. neuron. 2002;36(2):199\u2013211. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0896627302009698. Cited 2025 Feb 25","DOI":"10.1016\/S0896-6273(02)00969-8"},{"issue":"6","key":"1530_CR65","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.2337\/dbi21-0022","volume":"70","author":"LE Sewaybricker","year":"2021","unstructured":"Sewaybricker LE, Schur EA. Is bariatric surgery brain surgery? Diabetes US. 2021;70(6):1244\u20136.","journal-title":"Diabetes US"},{"issue":"2","key":"1530_CR66","doi-asserted-by":"publisher","first-page":"29","DOI":"10.15698\/cst2019.02.174","volume":"3","author":"F Seyfried","year":"2019","unstructured":"Seyfried F, Hankir MK. Could de-stressing the brain be the solution for long-term weight loss? Cell Stress. 2019;3(2):29\u201337.","journal-title":"Cell Stress"},{"issue":"40","key":"1530_CR67","doi-asserted-by":"publisher","first-page":"16199","DOI":"10.1073\/pnas.1306799110","volume":"110","author":"R Shirazi","year":"2013","unstructured":"Shirazi R, Palsdottir V, Collander J, Anesten F, Vogel H, Langlet F, et al. Glucagon-like peptide 1 receptor induced suppression of food intake, and body weight is mediated by central IL-1 and IL-6. Proc Natl Acad Sci. 2013;110(40):16199\u2013204.","journal-title":"Proc Natl Acad Sci"},{"key":"1530_CR68","doi-asserted-by":"publisher","first-page":"7279","DOI":"10.1038\/srep07279","volume":"4","author":"WY Tam","year":"2014","unstructured":"Tam WY, Ma CHE. Bipolar\/rod-shaped microglia are proliferating microglia with distinct M1\/M2 phenotypes. Sci Rep England. 2014;4:7279.","journal-title":"Sci Rep England"},{"key":"1530_CR69","doi-asserted-by":"crossref","unstructured":"Thaler JP, Yi C-X, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 2012;122(1):153\u201362. Available from: http:\/\/www.jci.org\/articles\/view\/59660. Cited 2025 Feb 25","DOI":"10.1172\/JCI59660"},{"key":"1530_CR70","doi-asserted-by":"crossref","unstructured":"Thomas K, Beyer F, Lewe G, Zhang R, Schindler S, Sch\u00f6nknecht P, et al. Higher body mass index is linked to altered hypothalamic microstructure. Sci Rep. 2019;9(1):17373. Available from: https:\/\/www.nature.com\/articles\/s41598-019-53578-4. Cited 2025 Feb 25","DOI":"10.1038\/s41598-019-53578-4"},{"issue":"2","key":"1530_CR71","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.celrep.2017.03.043","volume":"19","author":"K Timper","year":"2017","unstructured":"Timper K, Denson JL, Steculorum SM, Heilinger C, Engstr\u00f6m-Ruud L, Wunderlich CM, et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep. 2017;19(2):267\u201380.","journal-title":"Cell Rep"},{"key":"1530_CR72","doi-asserted-by":"publisher","first-page":"107527","DOI":"10.1016\/j.appet.2024.107527","volume":"200","author":"M Tweedale","year":"2024","unstructured":"Tweedale M, Morys F, Pastor-Bernier A, Azizi H, Tremblay C, Dagher A. Obesity and diffusion-weighted imaging of subcortical grey matter in young and older adults. Appetite England. 2024;200:107527.","journal-title":"Appetite England"},{"key":"1530_CR73","doi-asserted-by":"publisher","unstructured":"Uranga RM, Keller JN. The Complex Interactions Between Obesity, Metabolism and the Brain. Front Neurosci 2019;13:513 https:\/\/doi.org\/10.3389\/fnins.2019.00513\/full. Cited 2025 Feb 25","DOI":"10.3389\/fnins.2019.00513\/full"},{"issue":"1","key":"1530_CR74","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.cmet.2017.05.015","volume":"26","author":"M Valdearcos","year":"2017","unstructured":"Valdearcos M, Douglass JD, Robblee MM, Dorfman MD, Stifler DR, Bennett ML, et al. Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab. 2017;26(1):185-197.e3.","journal-title":"Cell Metab"},{"key":"1530_CR75","doi-asserted-by":"crossref","unstructured":"Valdearcos M, Douglass JD, Robblee MM, Dorfman MD, Stifler DR, Bennett ML, et al. Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab. 2017a;26(1):185\u2013197.e3. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S155041311730339X. Cited 2025 Feb 25","DOI":"10.1016\/j.cmet.2017.05.015"},{"key":"1530_CR76","doi-asserted-by":"crossref","unstructured":"Valdearcos M, Robblee MM, Benjamin DI, Nomura DK, Xu AW, Koliwad SK. Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. Cell Rep 2014;9(6):2124\u201338. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2211124714009723. Cited 2025 Feb 25","DOI":"10.1016\/j.celrep.2014.11.018"},{"key":"1530_CR77","doi-asserted-by":"crossref","unstructured":"Vukovi\u0107 M, Nosek I, Medi\u0107 Stojanoska M, Kozi\u0107 D. Neurometabolic and neuroinflammatory consequences of obesity: insights into brain vulnerability and imaging-based biomarkers. Int J Mol Sci Switzerland; 2026;27(2)","DOI":"10.3390\/ijms27020958"},{"issue":"1","key":"1530_CR78","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1016\/S0006-291X(02)00230-9","volume":"293","author":"K Wallenius","year":"2002","unstructured":"Wallenius K, Wallenius V, Sunter D, Dickson SL, Jansson J-O. Intracerebroventricular interleukin-6 treatment decreases body fat in rats. Biochem Biophys Res Commun US. 2002;293(1):560\u20135.","journal-title":"Biochem Biophys Res Commun US"},{"key":"1530_CR79","first-page":"222","volume":"563","author":"Z-J Wang","year":"2024","unstructured":"Wang Z-J, Han W-N, Chai S-F, Li Y, Fu C-J, Wang C-F, et al. Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP\/PS1\/tau mice. Neuroscience United States. 2024;563:222\u201334.","journal-title":"Neuroscience United States"},{"issue":"4","key":"1530_CR80","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1038\/nutd.2016.13","volume":"6","author":"S Weisberg","year":"2016","unstructured":"Weisberg S, Leibel R, Tortoriello DV. Proteasome inhibitors, including curcumin, improve pancreatic \u03b2-cell function and insulin sensitivity in diabetic mice. Nutr Diabetes England. 2016;6(4):205.","journal-title":"Nutr Diabetes England"},{"key":"1530_CR81","doi-asserted-by":"crossref","unstructured":"Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest 2005;115(5):1111\u20139. Available from: http:\/\/www.jci.org\/articles\/view\/25102. Cited 2025 Feb 25","DOI":"10.1172\/JCI25102"},{"key":"1530_CR82","doi-asserted-by":"crossref","unstructured":"Xu S, Feng Y, He W, Xu W, Xu W, Yang H, et al. Celastrol in metabolic diseases: Progress and application prospects. Pharmacol Res 2021;167;105572. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1043661821001560. Cited 2025 Feb 25","DOI":"10.1016\/j.phrs.2021.105572"},{"issue":"362","key":"1530_CR83","doi-asserted-by":"publisher","first-page":"123339","DOI":"10.1016\/j.lfs.2024.123339","volume":"1","author":"K Yang","year":"2025","unstructured":"Yang K, Wu Y, He Y, Dai J, Luo Y, Xie J, et al. GLP-1 and IL-6 regulates obesity in the gut and brain. Life Sci. 2025;1(362):123339.","journal-title":"Life Sci"},{"key":"1530_CR84","doi-asserted-by":"crossref","unstructured":"Yi C-X, Gericke M, Kr\u00fcger M, Alkemade A, Kabra DG, Hanske S, et al. High calorie diet triggers hypothalamic angiopathy. Mol Metab 2012;1(1\u20132):95\u2013100. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2212877812000130. Cited 2025 Feb 25","DOI":"10.1016\/j.molmet.2012.08.004"},{"key":"1530_CR85","doi-asserted-by":"crossref","unstructured":"Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKK\u03b2\/NF-\u03baB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008;135(1):61\u201373. Available from: https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0092867408010088. Cited 2025 Feb 25","DOI":"10.1016\/j.cell.2008.07.043"}],"container-title":["Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s10020-026-01530-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-026-01530-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s10020-026-01530-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T07:02:08Z","timestamp":1784012528000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s10020-026-01530-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,1]]},"references-count":87,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1530"],"URL":"https:\/\/doi.org\/10.1186\/s10020-026-01530-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-9344668\/v1","asserted-by":"object"}]},"ISSN":["1528-3658"],"issn-type":[{"value":"1528-3658","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,1]]},"assertion":[{"value":"7 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All animal handling protocols included in this work were performed by specialized personnel at our institute\u2019s animal facility (Reg. No. ES280790000188) and approved by the ethical committee of the Institute of Biomedical Research Sols-Morreale, CSIC and the Community of Madrid, complying with national (R.D. 53\/2013) and European Community guidelines (2010\/63\/UE) and with the ARRIVE guidelines (ethics approval number PROEX 288\/42).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Authors and their institutions consent on the publication of this work.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"111"}}