{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T02:04:04Z","timestamp":1772157844425,"version":"3.50.1"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":57,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2021\/01448-1"],"award-info":[{"award-number":["2021\/01448-1"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2021\/04664-7"],"award-info":[{"award-number":["2021\/04664-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2013\/07607-8"],"award-info":[{"award-number":["2013\/07607-8"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2021\/11189-3"],"award-info":[{"award-number":["2021\/11189-3"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006416","name":"Universidade Estadual De Campinas","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006416","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hypothalamic inflammation represents a central mechanism linking obesity to metabolic dysfunction. This process involves glial activation and persistent innate immune signaling, with Toll-like receptor 4 (TLR4) emerging as a critical interface between inflammatory pathways and impaired central insulin signaling. Irisin, a myokine released in response to physical exercise, has been shown to exert metabolic and anti-inflammatory effects in peripheral tissues, as well as neuroprotective actions in the brain. However, whether irisin directly modulates obesity-associated hypothalamic inflammation, particularly through TLR4-dependent pathways, remains unknown. Here, we investigated the effects of short-term intracerebroventricular delivery of recombinant irisin on hypothalamic inflammatory signaling in diet-induced obese mice. Central irisin administration reduced glial reactivity, downregulated components of the TLR4\/MyD88 pathway, and increased the expression of anti-inflammatory cytokines in the hypothalamus. In addition, irisin restored insulin-stimulated AKT phosphorylation and selectively reduced inguinal white adipose tissue mass without affecting overall body weight. Together, these findings indicate that central irisin administration attenuates obesity-related hypothalamic inflammation and modulates central insulin signaling, supporting a role for irisin as a regulator of neuroinflammation-linked metabolic dysfunction.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>Graphical abstract created with Biorender.com under publication license (MR296VUFQG).<\/jats:p>","DOI":"10.1007\/s12035-026-05729-8","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:43:14Z","timestamp":1772156594000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Central Irisin Administration Attenuates Hypothalamic TLR4\/MyD88-Mediated Neuroinflammatory Signaling in Diet-Induced Obese Mice"],"prefix":"10.1007","volume":"63","author":[{"given":"Kelly Cristina Pereira","family":"Bem","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tassiana Cristina","family":"Talpo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guilherme Augusto","family":"da Silva Nogueira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ariane Maria","family":"Zanesco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davi","family":"Sidarta-Oliveira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joel Alves","family":"da Silva Junior","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Carlos","family":"Boschero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Licio Augusto","family":"Velloso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena Cristina","family":"de Lima Barbosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"5729_CR1","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1016\/S0140-6736(23)02750-2","volume":"403","author":"NCD Risk Factor Collaboration (NCD-RisC)","year":"2024","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2024) Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet (London, England) 403:1027\u20131050. https:\/\/doi.org\/10.1016\/S0140-6736(23)02750-2","journal-title":"Lancet (London, England)"},{"key":"5729_CR2","doi-asserted-by":"publisher","DOI":"10.2147\/DMSO.S540103","volume":"18","author":"L Wang","year":"2025","unstructured":"Wang L, Wang Q, Xiong Y et al (2025) Obesity and its comorbidities: current treatment options, emerging biological mechanisms, future perspectives and challenges. Diabetes Metab Syndr Obes 18:3427. https:\/\/doi.org\/10.2147\/DMSO.S540103","journal-title":"Diabetes Metab Syndr Obes"},{"key":"5729_CR3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12992-019-0457-Y\/FIGURES\/4","volume":"15","author":"A Fox","year":"2019","unstructured":"Fox A, Feng W, Asal V (2019) What is driving global obesity trends? Globalization or \u201cmodernization\u201d? Glob Health 15:1\u201316. https:\/\/doi.org\/10.1186\/S12992-019-0457-Y\/FIGURES\/4","journal-title":"Glob Health"},{"issue":"6","key":"5729_CR4","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.1038\/s42255-024-01106-8","volume":"610","author":"F Magkos","year":"2024","unstructured":"Magkos F, S\u00f8rensen TIA, Raubenheimer D et al (2024) On the pathogenesis of obesity: causal models and missing pieces of the puzzle. Nat Metab 610(6):1856\u20131865. https:\/\/doi.org\/10.1038\/s42255-024-01106-8","journal-title":"Nat Metab"},{"key":"5729_CR5","doi-asserted-by":"publisher","unstructured":"Karczewski J, Zieli\u0144ska A, Staszewski R et al (2022) Obesity and the Brain. Int J Mol Sci 23. https:\/\/doi.org\/10.3390\/IJMS23116145","DOI":"10.3390\/IJMS23116145"},{"key":"5729_CR6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59660","volume":"122","author":"JP Thaler","year":"2012","unstructured":"Thaler JP, Yi CX, Schur EA et al (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153. https:\/\/doi.org\/10.1172\/JCI59660","journal-title":"J Clin Invest"},{"key":"5729_CR7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI88878","volume":"127","author":"A Jais","year":"2017","unstructured":"Jais A, Br\u00fcning JC (2017) Hypothalamic inflammation in obesity and metabolic disease. J Clin Invest 127:24. https:\/\/doi.org\/10.1172\/JCI88878","journal-title":"J Clin Invest"},{"key":"5729_CR8","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-01079-8","author":"O Le Thuc","year":"2024","unstructured":"Le Thuc O, Garc\u00eda-C\u00e1ceres C (2024) Obesity-induced inflammation: connecting the periphery to the brain. Nat Metab. https:\/\/doi.org\/10.1038\/s42255-024-01079-8","journal-title":"Nat Metab"},{"key":"5729_CR9","doi-asserted-by":"publisher","first-page":"4192","DOI":"10.1210\/EN.2004-1520","volume":"146","author":"CT De Souza","year":"2005","unstructured":"De Souza CT, Araujo EP, Bordin S et al (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192\u20134199. https:\/\/doi.org\/10.1210\/EN.2004-1520","journal-title":"Endocrinology"},{"key":"5729_CR10","doi-asserted-by":"publisher","unstructured":"Rogero MM, Calder PC (2018) Obesity, inflammation, toll-like receptor 4 and fatty acids. Nutrients 10. https:\/\/doi.org\/10.3390\/NU10040432","DOI":"10.3390\/NU10040432"},{"key":"5729_CR11","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1111\/J.1365-2567.2004.01976.X","volume":"113","author":"EM P\u00e5lsson-McDermott","year":"2004","unstructured":"P\u00e5lsson-McDermott EM, O\u2019Neill LAJ (2004) Signal transduction by the lipopolysaccharide receptor, toll-like receptor-4. Immunology 113:153. https:\/\/doi.org\/10.1111\/J.1365-2567.2004.01976.X","journal-title":"Immunology"},{"key":"5729_CR12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2760-08.2009","volume":"29","author":"M Milanski","year":"2009","unstructured":"Milanski M, Degasperi G, Coope A et al (2009) Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci 29:359. https:\/\/doi.org\/10.1523\/JNEUROSCI.2760-08.2009","journal-title":"J Neurosci"},{"key":"5729_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/J.MCE.2022.111676","volume":"552","author":"JJ Slate-Romano","year":"2022","unstructured":"Slate-Romano JJ, Yano N, Zhao TC (2022) Irisin reduces inflammatory signaling pathways in inflammation-mediated metabolic syndrome. Mol Cell Endocrinol 552:111676. https:\/\/doi.org\/10.1016\/J.MCE.2022.111676","journal-title":"Mol Cell Endocrinol"},{"key":"5729_CR14","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nature10777","volume":"481","author":"P Bostr\u00f6m","year":"2012","unstructured":"Bostr\u00f6m P, Wu J, Jedrychowski MP et al (2012) A PGC1-\u03b1-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nat 481:463\u2013468. https:\/\/doi.org\/10.1038\/nature10777","journal-title":"Nat"},{"key":"5729_CR15","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-020-00413-3","volume":"10","author":"F Rabiee","year":"2020","unstructured":"Rabiee F, Lachinani L, Ghaedi S et al (2020) New insights into the cellular activities of Fndc5\/Irisin and its signaling pathways. Cell Biosci 10:51. https:\/\/doi.org\/10.1186\/s13578-020-00413-3","journal-title":"Cell Biosci"},{"key":"5729_CR16","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/j.cmet.2013.09.008","volume":"18","author":"CD Wrann","year":"2013","unstructured":"Wrann CD, White JP, Salogiannnis J et al (2013) Exercise induces hippocampal BDNF through a PGC-1\u03b1\/FNDC5 pathway. Cell Metab 18:649\u2013659. https:\/\/doi.org\/10.1016\/j.cmet.2013.09.008","journal-title":"Cell Metab"},{"key":"5729_CR17","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1038\/s42255-021-00438-z","volume":"3","author":"MR Islam","year":"2021","unstructured":"Islam MR, Valaris S, Young MF et al (2021) Exercise hormone irisin is a critical regulator of cognitive function. Nat Metab 3:1058\u20131070. https:\/\/doi.org\/10.1038\/s42255-021-00438-z","journal-title":"Nat Metab"},{"key":"5729_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/S41591-018-0275-4","volume":"25","author":"MV Lourenco","year":"2019","unstructured":"Lourenco MV, Frozza RL, de Freitas GB et al (2019) Exercise-linked FNDC5\/irisin rescues synaptic plasticity and memory defects in Alzheimer\u2019s models. Nat Med 25:165. https:\/\/doi.org\/10.1038\/S41591-018-0275-4","journal-title":"Nat Med"},{"key":"5729_CR19","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1152\/AJPENDO.00308.2013\/ASSET\/IMAGES\/LARGE\/ZH10051470710004.JPEG","volume":"306","author":"MK Piya","year":"2014","unstructured":"Piya MK, Harte AL, Sivakumar K et al (2014) The identification of irisin in human cerebrospinal fluid: Influence of adiposity, metabolic markers, and gestational diabetes. Am J Physiol - Endocrinol Metab 306:512\u2013518. https:\/\/doi.org\/10.1152\/AJPENDO.00308.2013\/ASSET\/IMAGES\/LARGE\/ZH10051470710004.JPEG","journal-title":"Am J Physiol - Endocrinol Metab"},{"key":"5729_CR20","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/J.PEPTIDES.2018.03.013","volume":"103","author":"Q Ruan","year":"2018","unstructured":"Ruan Q, Zhang L, Ruan J et al (2018) Detection and quantitation of irisin in human cerebrospinal fluid by tandem mass spectrometry. Peptides 103:60\u201364. https:\/\/doi.org\/10.1016\/J.PEPTIDES.2018.03.013","journal-title":"Peptides"},{"key":"5729_CR21","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1016\/j.cmet.2015.08.001","volume":"22","author":"MP Jedrychowski","year":"2015","unstructured":"Jedrychowski MP, Wrann CD, Paulo JA et al (2015) Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab 22:734\u2013740. https:\/\/doi.org\/10.1016\/j.cmet.2015.08.001","journal-title":"Cell Metab"},{"key":"5729_CR22","doi-asserted-by":"publisher","unstructured":"Varela-Rodr\u00edguez BM, Pena-Bello L, Juiz-Vali\u00f1a P et al (2016) FNDC5 expression and circulating irisin levels are modified by diet and hormonal conditions in hypothalamus, adipose tissue and muscle. Sci Rep 6. https:\/\/doi.org\/10.1038\/SREP29898","DOI":"10.1038\/SREP29898"},{"key":"5729_CR23","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/J.NPEP.2015.06.004","volume":"52","author":"S Albayrak","year":"2015","unstructured":"Albayrak S, Atci IB, Kalayci M et al (2015) Effect of carnosine, methylprednisolone and their combined application on irisin levels in the plasma and brain of rats with acute spinal cord injury. Neuropeptides 52:47\u201354. https:\/\/doi.org\/10.1016\/J.NPEP.2015.06.004","journal-title":"Neuropeptides"},{"key":"5729_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2018.10.025","volume":"175","author":"H Kim","year":"2018","unstructured":"Kim H, Wrann CD, Jedrychowski M et al (2018) Irisin mediates effects on bone and fat via \u03b1V integrin receptors. Cell 175:1756. https:\/\/doi.org\/10.1016\/J.CELL.2018.10.025","journal-title":"Cell"},{"key":"5729_CR25","doi-asserted-by":"publisher","first-page":"3619","DOI":"10.1016\/j.neuron.2023.08.012","volume":"111","author":"E Kim","year":"2023","unstructured":"Kim E, Kim H, Jedrychowski MP et al (2023) Irisin reduces amyloid-\u03b2 by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron 111:3619-3633.e8. https:\/\/doi.org\/10.1016\/j.neuron.2023.08.012","journal-title":"Neuron"},{"key":"5729_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-022-02438-6","volume":"19","author":"Y Wang","year":"2022","unstructured":"Wang Y, Tian M, Tan J et al (2022) Irisin ameliorates neuroinflammation and neuronal apoptosis through integrin \u03b1V\u03b25\/AMPK signaling pathway after intracerebral hemorrhage in mice. J Neuroinflammation 19:1\u201320. https:\/\/doi.org\/10.1186\/s12974-022-02438-6","journal-title":"J Neuroinflammation"},{"key":"5729_CR27","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1038\/s41591-018-0275-4","volume":"25","author":"MV Lourenco","year":"2019","unstructured":"Lourenco MV, Frozza RL, de Freitas GB et al (2019) Exercise-linked FNDC5\/irisin rescues synaptic plasticity and memory defects in Alzheimer\u2019s models. Nat Med 25:165\u2013175. https:\/\/doi.org\/10.1038\/s41591-018-0275-4","journal-title":"Nat Med"},{"key":"5729_CR28","doi-asserted-by":"publisher","first-page":"58","DOI":"10.7499\/J.ISSN.1008-8830.2020.01.012","volume":"22","author":"XP Xu","year":"2020","unstructured":"Xu XP, Huang LY, Zhao FY et al (2020) Effect of irisin on hypoxic-ischemic brain damage in neonatal rats. Zhongguo Dang Dai Er Ke Za Zhi 22:58\u201364. https:\/\/doi.org\/10.7499\/J.ISSN.1008-8830.2020.01.012","journal-title":"Zhongguo Dang Dai Er Ke Za Zhi"},{"key":"5729_CR29","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.neulet.2015.03.069","volume":"595","author":"W Zhang","year":"2015","unstructured":"Zhang W, Chang L, Zhang C et al (2015) Irisin: a myokine with locomotor activity. Neurosci Lett 595:7\u201311. https:\/\/doi.org\/10.1016\/j.neulet.2015.03.069","journal-title":"Neurosci Lett"},{"key":"5729_CR30","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/J.EJPHAR.2016.09.011","volume":"791","author":"C Ferrante","year":"2016","unstructured":"Ferrante C, Orlando G, Recinella L et al (2016) Central inhibitory effects on feeding induced by the adipo-myokine irisin. Eur J Pharmacol 791:389\u2013394. https:\/\/doi.org\/10.1016\/J.EJPHAR.2016.09.011","journal-title":"Eur J Pharmacol"},{"key":"5729_CR31","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s10557-015-6580-y","volume":"29","author":"W Zhang","year":"2015","unstructured":"Zhang W, Chang L, Zhang C et al (2015) Central and peripheral irisin differentially regulate blood pressure. Cardiovasc Drugs Ther 29:121\u2013127. https:\/\/doi.org\/10.1007\/s10557-015-6580-y","journal-title":"Cardiovasc Drugs Ther"},{"key":"5729_CR32","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1016\/J.CELL.2018.06.021","volume":"174","author":"A Zeisel","year":"2018","unstructured":"Zeisel A, Hochgerner H, L\u00f6nnerberg P et al (2018) Molecular architecture of the mouse nervous system. Cell 174:999-1014.e22. https:\/\/doi.org\/10.1016\/J.CELL.2018.06.021","journal-title":"Cell"},{"key":"5729_CR33","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.1016\/J.CELREP.2017.03.004","volume":"18","author":"R Chen","year":"2017","unstructured":"Chen R, Wu X, Jiang L, Zhang Y (2017) Single-cell RNA-Seq reveals hypothalamic cell diversity. Cell Rep 18:3227. https:\/\/doi.org\/10.1016\/J.CELREP.2017.03.004","journal-title":"Cell Rep"},{"key":"5729_CR34","doi-asserted-by":"publisher","unstructured":"Yoo S, Cha D, Kim DW et al (2019) Tanycyte-Independent Control of Hypothalamic Leptin Signaling. Front Neurosci 13. https:\/\/doi.org\/10.3389\/FNINS.2019.00240\/FULL","DOI":"10.3389\/FNINS.2019.00240\/FULL"},{"key":"5729_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-020-76488-2","volume":"10","author":"D Sidarta-Oliveira","year":"2020","unstructured":"Sidarta-Oliveira D, Jara CP, Ferruzzi AJ et al (2020) SARS-CoV-2 receptor is co-expressed with elements of the kinin\u2013kallikrein, renin\u2013angiotensin and coagulation systems in alveolar cells. Sci Reports 10:1\u201319. https:\/\/doi.org\/10.1038\/s41598-020-76488-2","journal-title":"Sci Reports"},{"key":"5729_CR36","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/J.BBI.2019.12.012","volume":"87","author":"G Nogueira","year":"2020","unstructured":"Nogueira G, Solon C, Carraro RS et al (2020) Interleukin-17 acts in the hypothalamus reducing food intake. Brain Behav Immun 87:272\u2013285. https:\/\/doi.org\/10.1016\/J.BBI.2019.12.012","journal-title":"Brain Behav Immun"},{"key":"5729_CR37","volume-title":"Laboratory animal anaesthesia","author":"P Flecknell","year":"2016","unstructured":"Flecknell P (2016) Laboratory animal anaesthesia, 8th ed. Elsevier Inc","edition":"8th ed"},{"key":"5729_CR38","volume-title":"The mouse brain in stereotaxic coordinates","author":"G Paxinos","year":"2004","unstructured":"Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates, 2nd ed. Elsevier Inc","edition":"2nd ed"},{"key":"5729_CR39","doi-asserted-by":"publisher","first-page":"1549","DOI":"10.1007\/S11064-018-2569-9\/FIGURES\/6","volume":"43","author":"Y Asadi","year":"2018","unstructured":"Asadi Y, Gorjipour F, Behrouzifar S, Vakili A (2018) Irisin peptide protects brain against ischemic injury through reducing apoptosis and enhancing BDNF in a rodent model of stroke. Neurochem Res 43:1549\u20131560. https:\/\/doi.org\/10.1007\/S11064-018-2569-9\/FIGURES\/6","journal-title":"Neurochem Res"},{"key":"5729_CR40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/S12868-024-00884-X\/FIGURES\/7","volume":"25","author":"ZN Ozdemir-Kumral","year":"2024","unstructured":"Ozdemir-Kumral ZN, Akg\u00fcn T, Ha\u015fim C et al (2024) Intracerebroventricular administration of the exercise hormone irisin or acute strenuous exercise alleviates epileptic seizure-induced neuroinflammation and improves memory dysfunction in rats. BMC Neurosci 25:1\u201315. https:\/\/doi.org\/10.1186\/S12868-024-00884-X\/FIGURES\/7","journal-title":"BMC Neurosci"},{"key":"5729_CR41","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1079\/BJN19800066","volume":"43","author":"P Rogers","year":"1980","unstructured":"Rogers P, Webb GP (1980) Estimation of body fat in normal and obese mice. Br J Nutr 43:83\u201386. https:\/\/doi.org\/10.1079\/BJN19800066","journal-title":"Br J Nutr"},{"key":"5729_CR42","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1007\/S00125-008-0929-8\/FIGURES\/8","volume":"51","author":"H Tsuneki","year":"2008","unstructured":"Tsuneki H, Murata S, Anzawa Y et al (2008) Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice. Diabetologia 51:657\u2013667. https:\/\/doi.org\/10.1007\/S00125-008-0929-8\/FIGURES\/8","journal-title":"Diabetologia"},{"key":"5729_CR43","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.90377.2008","author":"KA Posey","year":"2009","unstructured":"Posey KA, Clegg DJ, Printz RL et al (2009) Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab. https:\/\/doi.org\/10.1152\/ajpendo.90377.2008","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"5729_CR44","doi-asserted-by":"publisher","first-page":"1996","DOI":"10.3390\/CELLS11131996\/S1","volume":"11","author":"AM Zanesco","year":"2022","unstructured":"Zanesco AM, Mendes NF, Engel DF et al (2022) Hypothalamic CREB regulates the expression of Pomc-processing enzyme Pcsk2. Cells 11:1996. https:\/\/doi.org\/10.3390\/CELLS11131996\/S1","journal-title":"Cells"},{"key":"5729_CR45","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.73","author":"TD Schmittgen","year":"2008","unstructured":"Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc. https:\/\/doi.org\/10.1038\/nprot.2008.73","journal-title":"Nat Protoc"},{"key":"5729_CR46","doi-asserted-by":"publisher","DOI":"10.3389\/FNINS.2018.00846","volume":"12","author":"NF Mendes","year":"2018","unstructured":"Mendes NF, Kim YB, Velloso LA, Ara\u00fajo EP (2018) Hypothalamic microglial activation in obesity: a mini-review. Front Neurosci 12:846. https:\/\/doi.org\/10.3389\/FNINS.2018.00846","journal-title":"Front Neurosci"},{"key":"5729_CR47","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/J.CELL.2010.01.022","volume":"140","author":"O Takeuchi","year":"2010","unstructured":"Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805\u2013820. https:\/\/doi.org\/10.1016\/J.CELL.2010.01.022","journal-title":"Cell"},{"key":"5729_CR48","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.3390\/BIOM11081109","volume":"11","author":"S Salucci","year":"2021","unstructured":"Salucci S, Bartoletti AS, Battistelli M et al (2021) How inflammation pathways contribute to cell death in neuro-muscular disorders. Biomol 11:1109. https:\/\/doi.org\/10.3390\/BIOM11081109","journal-title":"Biomol"},{"key":"5729_CR49","doi-asserted-by":"publisher","first-page":"441539","DOI":"10.3389\/FENDO.2019.00524","volume":"10","author":"R Villareal","year":"2019","unstructured":"Villareal R, Stocker CJ, Feraco A et al (2019) Irisin: a hope in understanding and managing obesity and metabolic syndrome. Front Endocrinol (Lausanne) 10:441539. https:\/\/doi.org\/10.3389\/FENDO.2019.00524","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"9","key":"5729_CR50","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/J.TEM.2022.06.003","volume":"33","author":"JF Bao","year":"2022","unstructured":"Bao JF, She QY, Hu PP et al (2022) Irisin, a fascinating field in our times. Trends Endocrinol Metab 33(9):601\u2013613. https:\/\/doi.org\/10.1016\/J.TEM.2022.06.003","journal-title":"Trends Endocrinol Metab"},{"key":"5729_CR51","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/6572342","author":"H Li","year":"2021","unstructured":"Li H, Wang F, Yang M et al (2021) The effect of irisin as a metabolic regulator and its therapeutic potential for obesity. Int J Endocrinol. https:\/\/doi.org\/10.1155\/2021\/6572342","journal-title":"Int J Endocrinol"},{"key":"5729_CR52","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.metabol.2013.09.013","volume":"63","author":"SA Polyzos","year":"2014","unstructured":"Polyzos SA, Kountouras J, Anastasilakis AD et al (2014) Irisin in patients with nonalcoholic fatty liver disease. Metabolism 63:207\u2013217. https:\/\/doi.org\/10.1016\/j.metabol.2013.09.013","journal-title":"Metabolism"},{"key":"5729_CR53","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.lfs.2016.09.023","volume":"165","author":"S Rocha-Rodrigues","year":"2016","unstructured":"Rocha-Rodrigues S, Rodr\u00edguez A, Gouveia AM et al (2016) Effects of physical exercise on myokines expression and brown adipose-like phenotype modulation in rats fed a high-fat diet. Life Sci 165:100\u2013108. https:\/\/doi.org\/10.1016\/j.lfs.2016.09.023","journal-title":"Life Sci"},{"issue":"Suppl 1","key":"5729_CR54","doi-asserted-by":"publisher","first-page":"S467","DOI":"10.1016\/j.dsx.2017.03.037","volume":"11","author":"M Shanaki","year":"2017","unstructured":"Shanaki M, Moradi N, Emamgholipour S et al (2017) Lower circulating irisin is associated with nonalcoholic fatty liver disease and type 2 diabetes. Diabetes Metab Syndr 11(Suppl 1):S467\u2013S472. https:\/\/doi.org\/10.1016\/j.dsx.2017.03.037","journal-title":"Diabetes Metab Syndr"},{"key":"5729_CR55","doi-asserted-by":"publisher","DOI":"10.3390\/biom11020322","author":"S Jiang","year":"2021","unstructured":"Jiang S, Piao L, Ma EB et al (2021) Associations of circulating irisin with FNDC5 expression in fat and muscle in type 1 and type 2 diabetic mice. Biomolecules. https:\/\/doi.org\/10.3390\/biom11020322","journal-title":"Biomolecules"},{"key":"5729_CR56","doi-asserted-by":"publisher","first-page":"E769","DOI":"10.1210\/jc.2012-2749","volume":"98","author":"JM Moreno-Navarrete","year":"2013","unstructured":"Moreno-Navarrete JM, Ortega F, Serrano M et al (2013) Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab 98:E769\u2013E778. https:\/\/doi.org\/10.1210\/jc.2012-2749","journal-title":"J Clin Endocrinol Metab"},{"key":"5729_CR57","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1684\/ecn.2020.0444","volume":"31","author":"E Dokumacioglu","year":"2020","unstructured":"Dokumacioglu E, Iskender H, Sahin A et al (2020) Serum levels of nesfatin-1 and irisin in obese children. Eur Cytokine Netw 31:39\u201343. https:\/\/doi.org\/10.1684\/ecn.2020.0444","journal-title":"Eur Cytokine Netw"},{"key":"5729_CR58","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/857270","volume":"2014","author":"M Pardo","year":"2014","unstructured":"Pardo M, Crujeiras AB, Amil M et al (2014) Association of irisin with fat mass, resting energy expenditure, and daily activity in conditions of extreme body mass index. Int J Endocrinol 2014:857270. https:\/\/doi.org\/10.1155\/2014\/857270","journal-title":"Int J Endocrinol"},{"key":"5729_CR59","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1111\/cen.12627","volume":"82","author":"AB Crujeiras","year":"2015","unstructured":"Crujeiras AB, Pardo M, Casanueva FF (2015) Irisin: \u2018fat\u2019 or artefact. Clin Endocrinol (Oxf) 82:467\u2013474. https:\/\/doi.org\/10.1111\/cen.12627","journal-title":"Clin Endocrinol (Oxf)"},{"key":"5729_CR60","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.bbi.2024.12.019","volume":"125","author":"J Wang","year":"2025","unstructured":"Wang J, Gao S, Fu S et al (2025) Irisin reprograms microglia through activation of STAT6 and prevents cognitive dysfunction after surgery in mice. Brain Behav Immun 125:68\u201391. https:\/\/doi.org\/10.1016\/j.bbi.2024.12.019","journal-title":"Brain Behav Immun"},{"key":"5729_CR61","doi-asserted-by":"publisher","first-page":"3458","DOI":"10.1016\/J.NEURON.2022.10.020","volume":"110","author":"RC Paolicelli","year":"2022","unstructured":"Paolicelli RC, Sierra A, Stevens B et al (2022) Microglia states and nomenclature: a field at its crossroads. Neuron 110:3458. https:\/\/doi.org\/10.1016\/J.NEURON.2022.10.020","journal-title":"Neuron"},{"key":"5729_CR62","doi-asserted-by":"publisher","DOI":"10.1016\/J.CMET.2023.07.008","volume":"35","author":"JD Douglass","year":"2023","unstructured":"Douglass JD, Ness KM, Valdearcos M et al (2023) Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance. Cell Metab 35:1613. https:\/\/doi.org\/10.1016\/J.CMET.2023.07.008","journal-title":"Cell Metab"},{"issue":"1","key":"5729_CR63","doi-asserted-by":"publisher","DOI":"10.1186\/S12974-024-03244-Y","volume":"21","author":"S Moon","year":"2024","unstructured":"Moon S, Park Y, Jang S et al (2024) Interleukin-2 improves insulin sensitivity through hypothalamic sympathetic activation in obese mice. J Neuroinflammation 21(1):250. https:\/\/doi.org\/10.1186\/S12974-024-03244-Y","journal-title":"J Neuroinflammation"},{"key":"5729_CR64","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1210\/ENDREV\/BNAC023","volume":"44","author":"LE Sewaybricker","year":"2023","unstructured":"Sewaybricker LE, Huang A, Chandrasekaran S et al (2023) The significance of hypothalamic inflammation and gliosis for the pathogenesis of obesity in humans. Endocr Rev 44:281\u2013296. https:\/\/doi.org\/10.1210\/ENDREV\/BNAC023","journal-title":"Endocr Rev"},{"key":"5729_CR65","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1007\/S12020-021-02875-Y\/FIGURES\/6","volume":"75","author":"S Zheng","year":"2022","unstructured":"Zheng S, Chen N, Kang X et al (2022) Irisin alleviates FFA induced \u03b2-cell insulin resistance and inflammatory response through activating PI3K\/AKT\/FOXO1 signaling pathway. Endocrine 75:740\u2013751. https:\/\/doi.org\/10.1007\/S12020-021-02875-Y\/FIGURES\/6","journal-title":"Endocrine"},{"key":"5729_CR66","doi-asserted-by":"publisher","unstructured":"Wang K, Li H, Wang H et al (2018) Irisin exerts neuroprotective effects on cultured neurons by regulating astrocytes. Mediators Inflamm. https:\/\/doi.org\/10.1155\/2018\/9070341","DOI":"10.1155\/2018\/9070341"},{"key":"5729_CR67","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1159\/000505961","volume":"49","author":"Q Yu","year":"2020","unstructured":"Yu Q, Li G, Ding Q et al (2020) Irisin protects brain against ischemia\/reperfusion injury through suppressing TLR4\/MyD88 pathway. Cerebrovasc Dis 49:346\u2013354. https:\/\/doi.org\/10.1159\/000505961","journal-title":"Cerebrovasc Dis"},{"key":"5729_CR68","doi-asserted-by":"publisher","first-page":"3306","DOI":"10.3390\/CELLS10123306\/S1","volume":"10","author":"W Zhu","year":"2021","unstructured":"Zhu W, Sahar NE, Javaid HMA et al (2021) Exercise-induced irisin decreases inflammation and improves NAFLD by competitive binding with MD2. Cells 10:3306. https:\/\/doi.org\/10.3390\/CELLS10123306\/S1","journal-title":"Cells"},{"key":"5729_CR69","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/J.CELL.2008.07.043","volume":"135","author":"X Zhang","year":"2008","unstructured":"Zhang X, Zhang G, Zhang H et al (2008) Hypothalamic IKKbeta\/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135:61\u201373. https:\/\/doi.org\/10.1016\/J.CELL.2008.07.043","journal-title":"Cell"},{"key":"5729_CR70","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.1016\/J.CELREP.2014.10.045","volume":"9","author":"E Tsaousidou","year":"2014","unstructured":"Tsaousidou E, Paeger L, Belgardt BF et al (2014) Distinct roles for JNK and IKK activation in Agouti-Related Peptide neurons in the development of obesity and insulin resistance. Cell Rep 9:1495\u20131506. https:\/\/doi.org\/10.1016\/J.CELREP.2014.10.045","journal-title":"Cell Rep"},{"key":"5729_CR71","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1101\/GAD.1878510","volume":"24","author":"G Sabio","year":"2010","unstructured":"Sabio G, Cavanagh-Kyros J, Barrett T et al (2010) Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1. Genes Dev 24:256\u2013264. https:\/\/doi.org\/10.1101\/GAD.1878510","journal-title":"Genes Dev"},{"key":"5729_CR72","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1016\/J.PEPTIDES.2007.03.006","volume":"28","author":"T Romanatto","year":"2007","unstructured":"Romanatto T, Cesquini M, Amaral ME et al (2007) TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient\u2013effects on leptin and insulin signaling pathways. Peptides 28:1050\u20131058. https:\/\/doi.org\/10.1016\/J.PEPTIDES.2007.03.006","journal-title":"Peptides"},{"key":"5729_CR73","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1038\/nri2449","volume":"8","author":"GS Hotamisligil","year":"2008","unstructured":"Hotamisligil GS, Erbay E (2008) Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8:923\u2013934. https:\/\/doi.org\/10.1038\/nri2449","journal-title":"Nat Rev Immunol"},{"key":"5729_CR74","doi-asserted-by":"publisher","first-page":"2992","DOI":"10.1172\/JCI34260","volume":"118","author":"S Schenk","year":"2008","unstructured":"Schenk S, Saberi M, Olefsky JM (2008) Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118:2992\u20133002. https:\/\/doi.org\/10.1172\/JCI34260","journal-title":"J Clin Invest"},{"key":"5729_CR75","doi-asserted-by":"publisher","DOI":"10.1016\/J.GENE.2020.145209","volume":"769","author":"R Song","year":"2021","unstructured":"Song R, Zhao X, Cao R et al (2021) Irisin improves insulin resistance by inhibiting autophagy through the PI3K\/Akt pathway in H9c2 cells. Gene 769:145209. https:\/\/doi.org\/10.1016\/J.GENE.2020.145209","journal-title":"Gene"},{"key":"5729_CR76","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PONE.0175498","volume":"12","author":"S Liu","year":"2017","unstructured":"Liu S, Du F, Li X et al (2017) Effects and underlying mechanisms of irisin on the proliferation and apoptosis of pancreatic \u03b2 cells. PLoS ONE 12:e0175498. https:\/\/doi.org\/10.1371\/JOURNAL.PONE.0175498","journal-title":"PLoS ONE"},{"key":"5729_CR77","doi-asserted-by":"publisher","first-page":"4985","DOI":"10.1002\/CPHY.C220030","volume":"13","author":"JW Willows","year":"2023","unstructured":"Willows JW, Blaszkiewicz M, Townsend KL (2023) The sympathetic innervation of adipose tissues: regulation, functions, and plasticity. Compr Physiol 13:4985. https:\/\/doi.org\/10.1002\/CPHY.C220030","journal-title":"Compr Physiol"},{"key":"5729_CR78","doi-asserted-by":"publisher","DOI":"10.3389\/FCELL.2022.979251\/FULL","volume":"10","author":"SC Puente-Ruiz","year":"2022","unstructured":"Puente-Ruiz SC, Jais A (2022) Reciprocal signaling between adipose tissue depots and the central nervous system. Front Cell Dev Biol 10:979251. https:\/\/doi.org\/10.3389\/FCELL.2022.979251\/FULL","journal-title":"Front Cell Dev Biol"},{"key":"5729_CR79","doi-asserted-by":"publisher","DOI":"10.62347\/AIWS5429","volume":"17","author":"W Shi","year":"2025","unstructured":"Shi W, Tan H, Liao C, An Z (2025) Cross-regulation between adipose tissue innervation and metaflammation: a potential therapeutic target for obesity. Am J Transl Res 17:4087. https:\/\/doi.org\/10.62347\/AIWS5429","journal-title":"Am J Transl Res"},{"key":"5729_CR80","doi-asserted-by":"publisher","DOI":"10.3389\/FNMOL.2022.1028223","volume":"15","author":"AE Autry","year":"2022","unstructured":"Autry AE (2022) Function of brain-derived neurotrophic factor in the hypothalamus: implications for depression pathology. Front Mol Neurosci 15:1028223. https:\/\/doi.org\/10.3389\/FNMOL.2022.1028223","journal-title":"Front Mol Neurosci"},{"key":"5729_CR81","doi-asserted-by":"publisher","DOI":"10.3389\/FNCEL.2019.00363\/XML\/NLM","volume":"13","author":"M Miranda","year":"2019","unstructured":"Miranda M, Morici JF, Zanoni MB, Bekinschtein P (2019) Brain-derived neurotrophic factor: a key molecule for memory in the healthy and the pathological brain. Front Cell Neurosci 13:472800. https:\/\/doi.org\/10.3389\/FNCEL.2019.00363\/XML\/NLM","journal-title":"Front Cell Neurosci"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-026-05729-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-026-05729-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-026-05729-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:43:18Z","timestamp":1772156598000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-026-05729-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":81,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["5729"],"URL":"https:\/\/doi.org\/10.1007\/s12035-026-05729-8","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"24 October 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 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":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical Trial Number"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interest"}}],"article-number":"473"}}