{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:20:55Z","timestamp":1790508055296,"version":"4.1.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the National Key R&D Program of China","award":["2021YFD1300404"],"award-info":[{"award-number":["2021YFD1300404"]}]},{"name":"Shenyang Governmental Science and Technology Program","award":["No. 22-316-2-02"],"award-info":[{"award-number":["No. 22-316-2-02"]}]},{"name":"China Agriculture Research System program","award":["CARS-41"],"award-info":[{"award-number":["CARS-41"]}]},{"name":"China Association for Science and Technology (CAST) Youth Talent Lifting Project\u2013Special Program for Doctoral Candidates"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Animal Sci Biotechnol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The phenomenon where excessive activation of branched-chain amino acid (BCAA) degrading enzymes caused by high concentrations of leucine (Leu) leads to a decrease in the overall concentration of BCAA [including isoleucine (Ile) and valine (Val)] is called BCAA antagonism. Although this phenomenon has long been widely studied, the specific mechanism of its occurrence is still poorly understood. In this study, we investigated the specific mechanism by which Val and Ile alleviate the antagonistic effect caused by high concentrations of Leu through influencing insulin function. First, the ratios of Ile and Val in the low-protein diet were adjusted up and down by 15% to observe the metabolic status of broilers at the end of the experiment (the experiment period was from 0 to 42\u00a0d). Subsequently, the physiological and biochemical changes related to antagonism were determined using transcriptome and lipid metabolome analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      When fed with a high concentration of Leu, restricting Ile or supplementing Val can effectively alleviate antagonism. Under conditions of excessive dietary Val supplementation, insulin levels remained stable, whereas blood glucose levels increased (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05), and liver fat accumulated predominantly as ceramides rather than triglycerides, thereby disrupting the insulin-mediated phosphatidylinositol 3-kinase\/protein kinase B signaling pathway (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05). Excessive dietary Ile promoted liver inflammation and interleukin-6 release (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05), which acted on the pancreas to enhance insulin secretion. Additionally, the glucagon content in the pancreas decreased (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05), while insulin and glucagon-like peptide-1 levels increased (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Supplementation of Val or restriction of Ile in low-protein diets could alleviate the BCAA antagonism caused by high Leu, which mainly achieved by influencing insulin function. These findings provide new insights in revealing the BCAA antagonism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1186\/s40104-025-01326-2","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:03:02Z","timestamp":1770768182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Isoleucine and valine regulate the BCAA antagonism by influencing insulin function in broiler chickens"],"prefix":"10.1186","volume":"17","author":[{"given":"Bin","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingkun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8577-4803","authenticated-orcid":false,"given":"Yuming","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"1326_CR1","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s40104-024-01108-2","volume":"15","author":"B Wang","year":"2024","unstructured":"Wang B, Zhang X, Liu Y, Gao M, Wang M, Wang Y, et al. Assessment of the dietary amino acid profiles and the relative biomarkers for amino acid balance in the low-protein diets for broiler chickens. J Anim Sci Biotechnol. 2024;15:157. https:\/\/doi.org\/10.1186\/s40104-024-01108-2.","journal-title":"J Anim Sci Biotechnol"},{"issue":"2","key":"1326_CR2","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.cmet.2018.10.013","volume":"29","author":"MD Neinast","year":"2019","unstructured":"Neinast MD, Jang C, Hui S, Murashige DS, Chu Q, Morscher RJ, et al. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metab. 2019;29(2):417-429.e4. https:\/\/doi.org\/10.1016\/j.cmet.2018.10.013.","journal-title":"Cell Metab"},{"key":"1326_CR3","doi-asserted-by":"publisher","first-page":"101198","DOI":"10.1016\/j.arr.2020.101198","volume":"64","author":"DG Le Couteur","year":"2020","unstructured":"Le Couteur DG, Solon-Biet SM, Cogger VC, Ribeiro R, de Cabo R, Raubenheimer D, et al. Branched chain amino acids, aging and age-related health. Ageing Res Rev. 2020;64:101198. https:\/\/doi.org\/10.1016\/j.arr.2020.101198.","journal-title":"Ageing Res Rev"},{"issue":"5","key":"1326_CR4","doi-asserted-by":"publisher","first-page":"833","DOI":"10.2337\/dc15-2251","volume":"39","author":"M Guasch-Ferr\u00e9","year":"2016","unstructured":"Guasch-Ferr\u00e9 M, Hruby A, Toledo E, Clish CB, Mart\u00ednez-Gonz\u00e1lez MA, Salas-Salvad\u00f3 J, et al. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis. Diabetes Care. 2016;39(5):833\u201346. https:\/\/doi.org\/10.2337\/dc15-2251.","journal-title":"Diabetes Care"},{"issue":"9","key":"1326_CR5","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1007\/s11306-017-1239-2","volume":"13","author":"J Liu","year":"2017","unstructured":"Liu J, Semiz S, van der Lee SJ, van der Spek A, Verhoeven A, van Klinken JB, et al. Metabolomics based markers predict type 2 diabetes in a 14-year follow-up study. Metabolomics. 2017;13(9):104. https:\/\/doi.org\/10.1007\/s11306-017-1239-2.","journal-title":"Metabolomics"},{"issue":"11","key":"1326_CR6","doi-asserted-by":"publisher","first-page":"E1175","DOI":"10.1152\/ajpendo.00630.2012","volume":"304","author":"DE Lackey","year":"2013","unstructured":"Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, et al. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab. 2013;304(11):E1175\u201387. https:\/\/doi.org\/10.1152\/ajpendo.00630.2012.","journal-title":"Am J Physiol Endocrinol Metab"},{"issue":"44","key":"1326_CR7","doi-asserted-by":"publisher","first-page":"18745","DOI":"10.1073\/pnas.0903032106","volume":"106","author":"DD Sears","year":"2009","unstructured":"Sears DD, Hsiao G, Hsiao A, Yu JG, Courtney CH, Ofrecio JM, et al. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization. Proc Natl Acad Sci USA. 2009;106(44):18745\u201350. https:\/\/doi.org\/10.1073\/pnas.0903032106.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"15","key":"1326_CR8","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1056\/NEJM196910092811503","volume":"281","author":"P Felig","year":"1969","unstructured":"Felig P, Marliss E, Cahill GF Jr. Plasma amino acid levels and insulin secretion in obesity. N Engl J Med. 1969;281(15):811\u20136. https:\/\/doi.org\/10.1056\/NEJM196910092811503.","journal-title":"N Engl J Med"},{"key":"1326_CR9","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1146\/annurev-physiol-020518-114455","volume":"81","author":"M Neinast","year":"2019","unstructured":"Neinast M, Murashige D, Arany Z. Branched chain amino acids. Annu Rev Physiol. 2019;81:139\u201364. https:\/\/doi.org\/10.1146\/annurev-physiol-020518-114455.","journal-title":"Annu Rev Physiol"},{"issue":"5","key":"1326_CR10","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/j.cmet.2014.09.003","volume":"20","author":"AC Shin","year":"2014","unstructured":"Shin AC, Fasshauer M, Filatova N, Grundell LA, Zielinski E, Zhou JY, et al. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism. Cell Metab. 2014;20(5):898\u2013909. https:\/\/doi.org\/10.1016\/j.cmet.2014.09.003.","journal-title":"Cell Metab"},{"issue":"1","key":"1326_CR11","doi-asserted-by":"publisher","first-page":"3508","DOI":"10.1038\/s41467-022-31249-9","volume":"13","author":"F Vanweert","year":"2022","unstructured":"Vanweert F, Neinast M, Tapia EE, van de Weijer T, Hoeks J, Schrauwen-Hinderling VB, et al. A randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes. Nat Commun. 2022;13:3508. https:\/\/doi.org\/10.1038\/s41467-022-31249-9.","journal-title":"Nat Commun"},{"issue":"4","key":"1326_CR12","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s42255-023-00794-y","volume":"5","author":"MC Blair","year":"2023","unstructured":"Blair MC, Neinast MD, Jang C, Chu Q, Jung JW, Axsom J, et al. Branched-chain amino acid catabolism in muscle affects systemic BCAA levels but not insulin resistance. Nat Metab. 2023;5(4):589\u2013606. https:\/\/doi.org\/10.1038\/s42255-023-00794-y.","journal-title":"Nat Metab"},{"issue":"48","key":"1326_CR13","doi-asserted-by":"publisher","first-page":"6347","DOI":"10.1038\/sj.onc.1209885","volume":"25","author":"MN Corradetti","year":"2006","unstructured":"Corradetti MN, Guan KL. Upstream of the mammalian target of rapamycin: do all roads pass through mTOR? Oncogene. 2006;25(48):6347\u201360. https:\/\/doi.org\/10.1038\/sj.onc.1209885.","journal-title":"Oncogene"},{"issue":"9","key":"1326_CR14","doi-asserted-by":"publisher","first-page":"2103","DOI":"10.1093\/jn\/135.9.2103","volume":"135","author":"M Doi","year":"2005","unstructured":"Doi M, Yamaoka I, Nakayama M, Mochizuki S, Sugahara K, Yoshizawa F. Isoleucine, a blood glucose-lowering amino acid, increases glucose uptake in rat skeletal muscle in the absence of increases in AMP-activated protein kinase activity. J Nutr. 2005;135(9):2103\u20138. https:\/\/doi.org\/10.1093\/jn\/135.9.2103.","journal-title":"J Nutr"},{"issue":"4","key":"1326_CR15","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nm.4057","volume":"22","author":"C Jang","year":"2016","unstructured":"Jang C, Oh SF, Wada S, Rowe GC, Liu L, Chan MC, et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat Med. 2016;22(4):421\u20136. https:\/\/doi.org\/10.1038\/nm.4057.","journal-title":"Nat Med"},{"key":"1326_CR16","unstructured":"Ministry of Agriculture and Rural Affairs of the People\u2019s Republic of China. Feeding standard of chickens. NY\/T33\u20132004. Beijing: China Agriculture Press; 2004."},{"issue":"8","key":"1326_CR17","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1007\/s00484-015-1114-7","volume":"60","author":"GL Yang","year":"2016","unstructured":"Yang GL, Zhang KY, Ding XM, Zheng P, Luo YH, Bai SP, et al. Effects of dietary DL-2-hydroxy-4(methylthio)butanoic acid supplementation on growth performance, indices of ascites syndrome, and antioxidant capacity of broilers reared at low ambient temperature. Int J Biometeorol. 2016;60(8):1193\u2013203. https:\/\/doi.org\/10.1007\/s00484-015-1114-7.","journal-title":"Int J Biometeorol"},{"issue":"11","key":"1326_CR18","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.2337\/dc08-0705","volume":"31","author":"ME Pennant","year":"2008","unstructured":"Pennant ME, Bluck LJ, Marcovecchio ML, Salgin B, Hovorka R, Dunger DB. Insulin administration and rate of glucose appearance in people with type 1 diabetes. Diabetes Care. 2008;31(11):2183\u20137. https:\/\/doi.org\/10.2337\/dc08-0705.","journal-title":"Diabetes Care"},{"issue":"14","key":"1326_CR19","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1016\/j.cmet.2016.04.022","volume":"23","author":"PM Titchenell","year":"2016","unstructured":"Titchenell PM, Quinn WJ, Lu M, Chu Q, Lu W, Li C, et al. Direct hepatocyte insulin signaling is required for lipogenesis but is dispensable for the suppression of glucose production. Cell Metab. 2016;23(14):1154\u201366. https:\/\/doi.org\/10.1016\/j.cmet.2016.04.022.","journal-title":"Cell Metab"},{"issue":"6","key":"1326_CR20","doi-asserted-by":"publisher","first-page":"e1700756","DOI":"10.1002\/mnfr.201700756","volume":"62","author":"NP Gannon","year":"2018","unstructured":"Gannon NP, Schnuck JK, Vaughan RA. BCAA Metabolism and Insulin Sensitivity - Dysregulated by Metabolic Status? Mol Nutr Food Res. 2018;62(6):e1700756. https:\/\/doi.org\/10.1002\/mnfr.201700756.","journal-title":"Mol Nutr Food Res"},{"issue":"4","key":"1326_CR21","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1016\/j.bbrc.2003.11.039","volume":"312","author":"M Doi","year":"2003","unstructured":"Doi M, Yamaoka I, Fukunaga T, Nakayama M. Isoleucine, a potent plasma glucose-lowering amino acid, stimulates glucose uptake in C2C12 myotubes. Biochem Biophys Res Commun. 2003;312(4):1111\u20137. https:\/\/doi.org\/10.1016\/j.bbrc.2003.11.039.","journal-title":"Biochem Biophys Res Commun"},{"key":"1326_CR22","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.fitote.2014.10.006","volume":"99","author":"AK Rawat","year":"2014","unstructured":"Rawat AK, Korthikunta V, Gautam S, Pal S, Tadigoppula N, Tamrakar AK, et al. 4-Hydroxyisoleucine improves insulin resistance by promoting mitochondrial biogenesis and act through AMPK and Akt dependent pathway. Fitoterapia. 2014;99:307\u201317. https:\/\/doi.org\/10.1016\/j.fitote.2014.10.006.","journal-title":"Fitoterapia"},{"issue":"8","key":"1326_CR23","first-page":"1427","volume":"61","author":"C Williams","year":"1977","unstructured":"Williams C, Alexander M, Glatstein EJ, Daniels JR. Role of radiation therapy in combination with chemotherapy in extensive oat cell cancer of the lung: a randomized study. Cancer Treat Rep. 1977;61(8):1427\u201331.","journal-title":"Cancer Treat Rep"},{"issue":"1","key":"1326_CR24","first-page":"6","volume":"66","author":"RR Arora","year":"1977","unstructured":"Arora RR, Gupta JP, Sabestian M. Epidemiological and virological study of a conjunctivitis epidemic in Delhi in 1975. Indian J Med Res. 1977;66(1):6\u201313.","journal-title":"Indian J Med Res"},{"key":"1326_CR25","doi-asserted-by":"publisher","first-page":"7215","DOI":"10.1038\/s41467-022-34747-y","volume":"13","author":"Y Wang","year":"2022","unstructured":"Wang Y, Luo M, Wang F, Tong Y, Li L, Shu Y, et al. AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis. Nat Commun. 2022;13:7215. https:\/\/doi.org\/10.1038\/s41467-022-34747-y.","journal-title":"Nat Commun"},{"issue":"2","key":"1326_CR26","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/s0092-8674(02)00808-5","volume":"110","author":"DH Kim","year":"2002","unstructured":"Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163\u201375. https:\/\/doi.org\/10.1016\/s0092-8674(02)00808-5.","journal-title":"Cell"},{"issue":"1","key":"1326_CR27","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1172\/JCI77812","volume":"126","author":"VT Samuel","year":"2016","unstructured":"Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1):12\u201322. https:\/\/doi.org\/10.1172\/JCI77812.","journal-title":"J Clin Invest"},{"issue":"1","key":"1326_CR28","doi-asserted-by":"publisher","first-page":"F75","DOI":"10.1152\/ajprenal.00185.2012","volume":"303","author":"V Schaeffer","year":"2012","unstructured":"Schaeffer V, Hansen KM, Morris DR, LeBoeuf RC, Abrass CK. RNA-binding protein IGF2BP2\/IMP2 is required for laminin-\u03b22 mRNA translation and is modulated by glucose concentration. Am J Physiol Renal Physiol. 2012;303(1):F75-82. https:\/\/doi.org\/10.1152\/ajprenal.00185.2012.","journal-title":"Am J Physiol Renal Physiol"},{"issue":"8","key":"1326_CR29","doi-asserted-by":"publisher","first-page":"2384","DOI":"10.7150\/thno.79493","volume":"13","author":"K Rubio","year":"2023","unstructured":"Rubio K, Romero-Olmedo AJ, Sarvari P, Swaminathan G, Ranvir VP, Rogel-Ayala DG, et al. Non-canonical integrin signaling activates EGFR and RAS-MAPK-ERK signaling in small cell lung cancer. Theranostics. 2023;13(8):2384\u2013407. https:\/\/doi.org\/10.7150\/thno.79493.","journal-title":"Theranostics"},{"issue":"6","key":"1326_CR30","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13150","volume":"19","author":"Y Jung","year":"2020","unstructured":"Jung Y, Kwon S, Ham S, Lee D, Park HH, Yamaoka Y, et al. Caenorhabditis elegans Lipin 1 moderates the lifespan-shortening effects of dietary glucose by maintaining \u03c9-6 polyunsaturated fatty acids. Aging Cell. 2020;19(6):e13150. https:\/\/doi.org\/10.1111\/acel.13150.","journal-title":"Aging Cell"},{"issue":"4","key":"1326_CR31","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1038\/s42255-023-00769-z","volume":"5","author":"K Wunderling","year":"2023","unstructured":"Wunderling K, Zurkovic J, Zink F, Kuerschner L, Thiele C. Triglyceride cycling enables modification of stored fatty acids. Nat Metab. 2023;5(4):699\u2013709. https:\/\/doi.org\/10.1038\/s42255-023-00769-z.","journal-title":"Nat Metab"},{"issue":"4","key":"1326_CR32","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1073\/pnas.1423952112","volume":"112","author":"DF Vatner","year":"2015","unstructured":"Vatner DF, Majumdar SK, Kumashiro N, Petersen MC, Rahimi Y, Gattu AK, et al. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proc Natl Acad Sci U S A. 2015;112(4):1143\u20138. https:\/\/doi.org\/10.1073\/pnas.1423952112.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1326_CR33","doi-asserted-by":"publisher","first-page":"104569","DOI":"10.1016\/j.ebiom.2023.104569","volume":"91","author":"MS Bjune","year":"2023","unstructured":"Bjune MS, Lawrence-Archer L, Laupsa-Borge J, Sommersten CH, McCann A, Glastad RC, et al. Metabolic role of the hepatic valine\/3-HIB pathway in fatty liver disease. EBioMedicine. 2023;91:104569. https:\/\/doi.org\/10.1016\/j.ebiom.2023.104569.","journal-title":"EBioMedicine"},{"issue":"52","key":"1326_CR34","doi-asserted-by":"publisher","first-page":"50230","DOI":"10.1074\/jbc.M200958200","volume":"277","author":"C Yu","year":"2002","unstructured":"Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002;277(52):50230\u20136. https:\/\/doi.org\/10.1074\/jbc.M200958200.","journal-title":"J Biol Chem"},{"issue":"29","key":"1326_CR35","doi-asserted-by":"publisher","first-page":"25847","DOI":"10.1074\/jbc.R200008200","volume":"277","author":"YA Hannun","year":"2002","unstructured":"Hannun YA, Obeid LM. The ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind. J Biol Chem. 2002;277(29):25847\u201350. https:\/\/doi.org\/10.1074\/jbc.R200008200.","journal-title":"J Biol Chem"},{"issue":"3","key":"1326_CR36","doi-asserted-by":"publisher","first-page":"591","DOI":"10.2337\/diabetes.54.3.591","volume":"54","author":"SA Summers","year":"2005","unstructured":"Summers SA, Nelson DH. A role for sphingolipids in producing the common features of type 2 diabetes, metabolic syndrome X, and Cushing\u2019s syndrome. Diabetes. 2005;54(3):591\u2013602. https:\/\/doi.org\/10.2337\/diabetes.54.3.591.","journal-title":"Diabetes"},{"issue":"3","key":"1326_CR37","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.cmet.2007.01.002","volume":"5","author":"WL Holland","year":"2007","unstructured":"Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 2007;5(3):167\u201379. https:\/\/doi.org\/10.1016\/j.cmet.2007.01.002.","journal-title":"Cell Metab"},{"issue":"2","key":"1326_CR38","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1124\/pr.57.2.5","volume":"57","author":"SM Foord","year":"2005","unstructured":"Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, et al. International union of pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev. 2005;57(2):279\u201388. https:\/\/doi.org\/10.1124\/pr.57.2.5.","journal-title":"Pharmacol Rev"},{"issue":"1","key":"1326_CR39","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.molcel.2016.08.026","volume":"64","author":"MV Gammons","year":"2016","unstructured":"Gammons MV, Renko M, Johnson CM, Rutherford TJ, Bienz M. Wnt signalosome assembly by DEP domain swapping of Dishevelled. Mol Cell. 2016;64(1):92\u2013104. https:\/\/doi.org\/10.1016\/j.molcel.2016.08.026.","journal-title":"Mol Cell"},{"issue":"9","key":"1326_CR40","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/nri.2017.52","volume":"17","author":"SC Sun","year":"2017","unstructured":"Sun SC. The non-canonical NF-\u03baB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17(9):545\u201358. https:\/\/doi.org\/10.1038\/nri.2017.52.","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"1326_CR41","doi-asserted-by":"publisher","first-page":"a001651","DOI":"10.1101\/cshperspect.a001651","volume":"1","author":"T Lawrence","year":"2009","unstructured":"Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651. https:\/\/doi.org\/10.1101\/cshperspect.a001651.","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"4","key":"1326_CR42","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.ccr.2013.03.009","volume":"23","author":"Z Xiao","year":"2013","unstructured":"Xiao Z, Jiang Q, Willette-Brown J, Xi S, Zhu F, Burkett S, et al. The pivotal role of IKK\u03b1 in the development of spontaneous lung squamous cell carcinomas. Cancer Cell. 2013;23(4):527\u201340. https:\/\/doi.org\/10.1016\/j.ccr.2013.03.009.","journal-title":"Cancer Cell"},{"key":"1326_CR43","doi-asserted-by":"publisher","first-page":"155641","DOI":"10.1016\/j.metabol.2023.155641","volume":"146","author":"W Chen","year":"2023","unstructured":"Chen W, Cui W, Wu J, Zheng W, Sun X, Zhang J, et al. Blocking IL-6 signaling improves glucose tolerance via SLC39A5-mediated suppression of glucagon secretion. Metabolism. 2023;146:155641. https:\/\/doi.org\/10.1016\/j.metabol.2023.155641.","journal-title":"Metabolism"},{"key":"1326_CR44","doi-asserted-by":"publisher","first-page":"103062","DOI":"10.1016\/j.ebiom.2020.103062","volume":"61","author":"N Bowker","year":"2020","unstructured":"Bowker N, Shah RL, Sharp SJ, Luan J, Stewart ID, Wheeler E, et al. Meta-analysis investigating the role of interleukin-6 mediated inflammation in type 2 diabetes. EBioMedicine. 2020;61:103062. https:\/\/doi.org\/10.1016\/j.ebiom.2020.103062.","journal-title":"EBioMedicine"},{"issue":"2","key":"1326_CR45","doi-asserted-by":"publisher","first-page":"537","DOI":"10.2337\/db10-0796","volume":"60","author":"T Suzuki","year":"2011","unstructured":"Suzuki T, Imai J, Yamada T, Ishigaki Y, Kaneko K, Uno K, et al. Interleukin-6 enhances glucose-stimulated insulin secretion from pancreatic beta-cells: potential involvement of the PLC-IP3-dependent pathway. Diabetes. 2011;60(2):537\u201347. https:\/\/doi.org\/10.2337\/db10-0796.","journal-title":"Diabetes"},{"issue":"11","key":"1326_CR46","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1038\/nm.2513","volume":"17","author":"H Ellingsgaard","year":"2011","unstructured":"Ellingsgaard H, Hauselmann I, Schuler B, Habib AM, Baggio LL, Meier DT, et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med. 2011;17(11):1481\u20139. https:\/\/doi.org\/10.1038\/nm.2513.","journal-title":"Nat Med"}],"container-title":["Journal of Animal Science and Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40104-025-01326-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40104-025-01326-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40104-025-01326-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:03:05Z","timestamp":1770768185000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s40104-025-01326-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1326"],"URL":"https:\/\/doi.org\/10.1186\/s40104-025-01326-2","relation":{},"ISSN":["2049-1891"],"issn-type":[{"value":"2049-1891","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]},"assertion":[{"value":"3 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 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":"This animal study was approved by the Ethics Management Committee of China Agricultural University (AW61504202-1-2).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that there is no conflict of interest regarding the publication of this article.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"27"}}