{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T06:23:57Z","timestamp":1792736637822,"version":"4.5.0"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T00:00:00Z","timestamp":1732752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Ministry of Economy and Competitiveness | Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID-2021-122766OB-100"],"award-info":[{"award-number":["PID-2021-122766OB-100"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Ministry of Economy and Competitiveness | Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018-094052-B-100"],"award-info":[{"award-number":["RTI2018-094052-B-100"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Ministry of Economy and Competitiveness | Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID-2021-122766OB-100"],"award-info":[{"award-number":["PID-2021-122766OB-100"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012818","name":"Comunidad de Madrid","doi-asserted-by":"publisher","award":["P2022\/BMD-7227"],"award-info":[{"award-number":["P2022\/BMD-7227"]}],"id":[{"id":"10.13039\/100012818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012818","name":"Comunidad de Madrid","doi-asserted-by":"publisher","award":["P2022\/BMD-7227"],"award-info":[{"award-number":["P2022\/BMD-7227"]}],"id":[{"id":"10.13039\/100012818","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"DOI":"10.1038\/s41467-024-54080-w","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T08:46:50Z","timestamp":1732783610000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The dual GLP-1\/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3239-4898","authenticated-orcid":false,"given":"M. Pilar","family":"Valdecantos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3803-9149","authenticated-orcid":false,"given":"Cintia","family":"Folgueira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6731-2098","authenticated-orcid":false,"given":"Patricia","family":"Rada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6607-7973","authenticated-orcid":false,"given":"Beatriz","family":"Gomez-Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7670-3237","authenticated-orcid":false,"given":"Maite","family":"Solas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana B.","family":"Hitos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9387-026X","authenticated-orcid":false,"given":"Joss","family":"Field","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Francisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Escalona-Garrido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebasti\u00e1n","family":"Zagmutt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Calderon-Dominguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Mera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma","family":"Garcia-Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Maym\u00f3-Masip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Grajales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Alen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-4836","authenticated-orcid":false,"given":"Alfonso","family":"Mora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neira","family":"S\u00e1inz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Vides-Urrestarazu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuria","family":"Vilarrasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Arbones-Mainar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1706-8592","authenticated-orcid":false,"given":"Carlos","family":"Zaragoza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda J.","family":"Moreno-Aliaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-1755","authenticated-orcid":false,"given":"Patricia","family":"Aspichueta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2906-3788","authenticated-orcid":false,"given":"Sonia","family":"Fern\u00e1ndez-Veledo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6994-6115","authenticated-orcid":false,"given":"Joan","family":"Vendrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4936-4206","authenticated-orcid":false,"given":"Dolors","family":"Serra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4244-4673","authenticated-orcid":false,"given":"Laura","family":"Herrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3475-157X","authenticated-orcid":false,"given":"Renate","family":"Schreiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Zechner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Sabio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3354-2768","authenticated-orcid":false,"given":"David","family":"Hornigold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina M.","family":"Rondinone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7660-8467","authenticated-orcid":false,"given":"Lutz","family":"Jermutus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Grimsby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1192-9045","authenticated-orcid":false,"given":"\u00c1ngela M.","family":"Valverde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,28]]},"reference":[{"key":"54080_CR1","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1007\/s00125-017-4354-8","volume":"60","author":"MA Sanchez-Garrido","year":"2017","unstructured":"Sanchez-Garrido, M. A. et al. GLP-1\/glucagon receptor co-agonism for treatment of obesity. Diabetologia 60, 1851\u20131861 (2017).","journal-title":"Diabetologia"},{"key":"54080_CR2","doi-asserted-by":"crossref","unstructured":"Nielsen, M. S. et al. Oxyntomodulin and glicentin may predict the effect of bariatric surgery on food preferences and weight loss. J. Clin. Endocrinol. Metab. 105, 1064\u20131074 (2020).","DOI":"10.1210\/clinem\/dgaa061"},{"key":"54080_CR3","doi-asserted-by":"publisher","first-page":"153997","DOI":"10.1016\/j.metabol.2019.153997","volume":"101","author":"N Perakakis","year":"2019","unstructured":"Perakakis, N. et al. Circulating levels of gastrointestinal hormones in response to the most common types of bariatric surgery and predictive value for weight loss over one year: evidence from two independent trials. Metabolism 101, 153997 (2019).","journal-title":"Metabolism"},{"key":"54080_CR4","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/0167-0115(88)90099-7","volume":"21","author":"FG Baldissera","year":"1988","unstructured":"Baldissera, F. G., Holst, J. J., Knuhtsen, S., Hilsted, L. & Nielsen, O. V. Oxyntomodulin (glicentin-(33-69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs. Regul. Pept. 21, 151\u2013166 (1988).","journal-title":"Regul. Pept."},{"key":"54080_CR5","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1111\/j.1365-2362.1988.tb01046.x","volume":"18","author":"BT Schjoldager","year":"1988","unstructured":"Schjoldager, B. T., Baldissera, F. G., Mortensen, P. E., Holst, J. J. & Christiansen, J. Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man. Eur. J. Clin. Invest. 18, 499\u2013503 (1988).","journal-title":"Eur. J. Clin. Invest."},{"key":"54080_CR6","doi-asserted-by":"publisher","first-page":"2258","DOI":"10.2337\/db09-0278","volume":"58","author":"A Pocai","year":"2009","unstructured":"Pocai, A. et al. Glucagon-like peptide 1\/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258\u20132266 (2009).","journal-title":"Diabetes"},{"key":"54080_CR7","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1002\/bip.22072","volume":"98","author":"JW Day","year":"2012","unstructured":"Day, J. W. et al. Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents. Biopolymers 98, 443\u2013450 (2012).","journal-title":"Biopolymers"},{"key":"54080_CR8","doi-asserted-by":"publisher","DOI":"10.1111\/cob.12433","volume":"11","author":"NA Di Prospero","year":"2021","unstructured":"Di Prospero, N. A. et al. Efficacy and safety of glucagon-like peptide-1\/glucagon receptor co-agonist JNJ-64565111 in individuals with type 2 diabetes mellitus and obesity: a randomized dose-ranging study. Clin. Obes. 11, e12433 (2021).","journal-title":"Clin. Obes."},{"key":"54080_CR9","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/nchembio.209","volume":"5","author":"JW Day","year":"2009","unstructured":"Day, J. W. et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat. Chem. Biol. 5, 749\u2013757 (2009).","journal-title":"Nat. Chem. Biol."},{"key":"54080_CR10","doi-asserted-by":"publisher","first-page":"101633","DOI":"10.1016\/j.molmet.2022.101633","volume":"66","author":"T Zimmermann","year":"2022","unstructured":"Zimmermann, T. et al. BI 456906: discovery and preclinical pharmacology of a novel GCGR\/GLP-1R dual agonist with robust anti-obesity efficacy. Mol. Metab. 66, 101633 (2022).","journal-title":"Mol. Metab."},{"key":"54080_CR11","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1111\/dom.14948","volume":"25","author":"A Jungnik","year":"2023","unstructured":"Jungnik, A. et al. Phase I studies of the safety, tolerability, pharmacokinetics and pharmacodynamics of the dual glucagon receptor\/glucagon-like peptide-1 receptor agonist BI 456906. Diabetes Obes. Metab. 25, 1011\u20131023 (2023).","journal-title":"Diabetes Obes. Metab."},{"key":"54080_CR12","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2020.117651","volume":"253","author":"Z Pei","year":"2020","unstructured":"Pei, Z. et al. Design and characterization of novel oxyntomodulin derivatives with potent dual GLP-1\/glucagon receptor activation and prolonged antidiabetic effects. Life Sci. 253, 117651 (2020).","journal-title":"Life Sci."},{"key":"54080_CR13","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1002\/hep.28962","volume":"65","author":"MP Valdecantos","year":"2017","unstructured":"Valdecantos, M. P. et al. A novel glucagon-like peptide 1\/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. Hepatology 65, 950\u2013968 (2017).","journal-title":"Hepatology"},{"key":"54080_CR14","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/s42255-020-0209-6","volume":"2","author":"ML Boland","year":"2020","unstructured":"Boland, M. L. et al. Resolution of NASH and hepatic fibrosis by the GLP-1R\/GcgR dual-agonist Cotadutide via modulating mitochondrial function and lipogenesis. Nat. Metab. 2, 413\u2013431 (2020).","journal-title":"Nat. Metab."},{"key":"54080_CR15","doi-asserted-by":"crossref","unstructured":"Marcondes-de-Castro, I. A. et al. Cotadutide effect in liver and adipose tissue in obese mice. J. Mol. Endocrinol. 70, e220168 (2023).","DOI":"10.1530\/JME-22-0168"},{"key":"54080_CR16","doi-asserted-by":"publisher","first-page":"2607","DOI":"10.1016\/S0140-6736(18)30726-8","volume":"391","author":"P Ambery","year":"2018","unstructured":"Ambery, P. et al. MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 391, 2607\u20132618 (2018).","journal-title":"Lancet"},{"key":"54080_CR17","doi-asserted-by":"crossref","unstructured":"Parker, V. E. R. et al. Efficacy, safety, and mechanistic insights of cotadutide, a dual receptor glucagon-like peptide-1 and glucagon agonist. J. Clin. Endocrinol. Metab. 105, dgz047 (2020).","DOI":"10.1210\/clinem\/dgz047"},{"key":"54080_CR18","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.2337\/dc20-2151","volume":"44","author":"R Nahra","year":"2021","unstructured":"Nahra, R. et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 44, 1433\u20131442 (2021).","journal-title":"Diabetes Care"},{"key":"54080_CR19","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1056\/NEJMoa2206038","volume":"387","author":"AM Jastreboff","year":"2022","unstructured":"Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205\u2013216 (2022).","journal-title":"N. Engl. J. Med."},{"key":"54080_CR20","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1016\/j.cmet.2022.07.013","volume":"34","author":"T Coskun","year":"2022","unstructured":"Coskun, T. et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 34, 1234\u20131247.e1239 (2022).","journal-title":"Cell Metab."},{"key":"54080_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2022.101533","volume":"63","author":"PJ Knerr","year":"2022","unstructured":"Knerr, P. J. et al. Next generation GLP-1\/GIP\/glucagon triple agonists normalize body weight in obese mice. Mol. Metab. 63, 101533 (2022).","journal-title":"Mol. Metab."},{"key":"54080_CR22","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1056\/NEJMoa2301972","volume":"389","author":"AM Jastreboff","year":"2023","unstructured":"Jastreboff, A. M., Kaplan, L. M. & Hartman, M. L. Triple-hormone-receptor agonist retatrutide for obesity. Reply. N. Engl. J. Med. 389, 1629\u20131630 (2023).","journal-title":"N. Engl. J. Med."},{"key":"54080_CR23","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101392","volume":"55","author":"BB Boland","year":"2022","unstructured":"Boland, B. B. et al. Peptide-YY(3-36)\/glucagon-like peptide-1 combination treatment of obese diabetic mice improves insulin sensitivity associated with recovered pancreatic beta-cell function and synergistic activation of discrete hypothalamic and brainstem neuronal circuitries. Mol. Metab. 55, 101392 (2022).","journal-title":"Mol. Metab."},{"key":"54080_CR24","doi-asserted-by":"publisher","first-page":"1292","DOI":"10.1016\/j.cell.2014.03.066","volume":"157","author":"Y Qiu","year":"2014","unstructured":"Qiu, Y. et al. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157, 1292\u20131308 (2014).","journal-title":"Cell"},{"key":"54080_CR25","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.cmet.2016.08.003","volume":"24","author":"L Lynch","year":"2016","unstructured":"Lynch, L. et al. iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24, 510\u2013519 (2016).","journal-title":"Cell Metab."},{"key":"54080_CR26","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1016\/j.cmet.2018.06.020","volume":"28","author":"M Heine","year":"2018","unstructured":"Heine, M. et al. Lipolysis triggers a systemic insulin response essential for efficient energy replenishment of activated brown adipose tissue in mice. Cell Metab. 28, 644\u2013655 e644 (2018).","journal-title":"Cell Metab."},{"key":"54080_CR27","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1016\/j.cmet.2007.05.002","volume":"5","author":"MK Badman","year":"2007","unstructured":"Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426\u2013437 (2007).","journal-title":"Cell Metab."},{"key":"54080_CR28","doi-asserted-by":"publisher","first-page":"5239","DOI":"10.1074\/jbc.M116.762922","volume":"292","author":"KM Alonge","year":"2017","unstructured":"Alonge, K. M., Meares, G. P. & Hillgartner, F. B. Glucagon and insulin cooperatively stimulate fibroblast growth factor 21 gene transcription by increasing the expression of activating transcription factor 4. J. Biol. Chem. 292, 5239\u20135252 (2017).","journal-title":"J. Biol. Chem."},{"key":"54080_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14069-2","volume":"11","author":"S Keipert","year":"2020","unstructured":"Keipert, S. et al. Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice. Nat. Commun. 11, 624 (2020).","journal-title":"Nat. Commun."},{"key":"54080_CR30","doi-asserted-by":"publisher","first-page":"2235","DOI":"10.1007\/s11695-017-2669-7","volume":"27","author":"A Casajoana","year":"2017","unstructured":"Casajoana, A. et al. Predictive value of gut peptides in T2D remission: randomized controlled trial comparing metabolic gastric bypass, sleeve gastrectomy and greater curvature plication. Obes. Surg. 27, 2235\u20132245 (2017).","journal-title":"Obes. Surg."},{"key":"54080_CR31","doi-asserted-by":"publisher","first-page":"e111418","DOI":"10.1371\/journal.pone.0111418","volume":"9","author":"AC Thompson","year":"2014","unstructured":"Thompson, A. C. et al. Fibroblast growth factor 21 is not required for the reductions in circulating insulin-like growth factor-1 or global cell proliferation rates in response to moderate calorie restriction in adult mice. PLoS ONE 9, e111418 (2014).","journal-title":"PLoS ONE"},{"key":"54080_CR32","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/nm1557","volume":"13","author":"T Yamauchi","year":"2007","unstructured":"Yamauchi, T. et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332\u2013339 (2007).","journal-title":"Nat. Med."},{"key":"54080_CR33","doi-asserted-by":"publisher","first-page":"E389","DOI":"10.1152\/ajpendo.00078.2022","volume":"323","author":"A Vasileva","year":"2022","unstructured":"Vasileva, A., Marx, T., Beaudry, J. L. & Stern, J. H. Glucagon receptor signaling at white adipose tissue does not regulate lipolysis. Am. J. Physiol. Endocrinol. Metab. 323, E389\u2013E401 (2022).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"54080_CR34","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1007\/s00125-006-0481-3","volume":"50","author":"SL Conarello","year":"2007","unstructured":"Conarello, S. L. et al. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 50, 142\u2013150 (2007).","journal-title":"Diabetologia"},{"key":"54080_CR35","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/nchembio.1359","volume":"9","author":"N Mayer","year":"2013","unstructured":"Mayer, N. et al. Development of small-molecule inhibitors targeting adipose triglyceride lipase. Nat. Chem. Biol. 9, 785\u2013787 (2013).","journal-title":"Nat. Chem. Biol."},{"key":"54080_CR36","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.soard.2018.03.003","volume":"14","author":"JJ Holst","year":"2018","unstructured":"Holst, J. J. et al. Mechanisms in bariatric surgery: gut hormones, diabetes resolution, and weight loss. Surg. Obes. Relat. Dis. 14, 708\u2013714 (2018).","journal-title":"Surg. Obes. Relat. Dis."},{"key":"54080_CR37","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.molmet.2013.12.001","volume":"3","author":"A Pocai","year":"2014","unstructured":"Pocai, A. Action and therapeutic potential of oxyntomodulin. Mol. Metab. 3, 241\u2013251 (2014).","journal-title":"Mol. Metab."},{"key":"54080_CR38","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1136\/bmjdrc-2019-001076","volume":"8","author":"K Alexiadou","year":"2020","unstructured":"Alexiadou, K. et al. Proglucagon peptide secretion profiles in type 2 diabetes before and after bariatric surgery: 1-year prospective study. BMJ Open Diabetes Res. Care 8, 1076 (2020).","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"54080_CR39","doi-asserted-by":"publisher","first-page":"1438","DOI":"10.1073\/pnas.0237106100","volume":"100","author":"RW Gelling","year":"2003","unstructured":"Gelling, R. W. et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc. Natl Acad. Sci. USA 100, 1438\u20131443 (2003).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"54080_CR40","doi-asserted-by":"publisher","first-page":"R27","DOI":"10.1152\/ajpregu.00288.2018","volume":"316","author":"A Tura","year":"2019","unstructured":"Tura, A., Pacini, G., Yamada, Y., Seino, Y. & Ahren, B. Glucagon and insulin secretion, insulin clearance, and fasting glucose in GIP receptor and GLP-1 receptor knockout mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 316, R27\u2013R37 (2019).","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"54080_CR41","doi-asserted-by":"publisher","first-page":"8649","DOI":"10.1073\/pnas.1705287114","volume":"114","author":"BP Leitner","year":"2017","unstructured":"Leitner, B. P. et al. Mapping of human brown adipose tissue in lean and obese young men. Proc. Natl Acad. Sci. USA 114, 8649\u20138654 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"54080_CR42","doi-asserted-by":"publisher","first-page":"5670","DOI":"10.1210\/en.2008-0336","volume":"149","author":"A Maida","year":"2008","unstructured":"Maida, A., Lovshin, J. A., Baggio, L. L. & Drucker, D. J. The glucagon-like peptide-1 receptor agonist oxyntomodulin enhances beta-cell function but does not inhibit gastric emptying in mice. Endocrinology 149, 5670\u20135678 (2008).","journal-title":"Endocrinology"},{"key":"54080_CR43","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.2337\/diabetes.48.8.1543","volume":"48","author":"M Komatsu","year":"1999","unstructured":"Komatsu, M. et al. Augmentation of Ca2+-stimulated insulin release by glucose and long-chain fatty acids in rat pancreatic islets: free fatty acids mimic ATP-sensitive K+ channel-independent insulinotropic action of glucose. Diabetes 48, 1543\u20131549 (1999).","journal-title":"Diabetes"},{"key":"54080_CR44","first-page":"2085","volume":"86","author":"CH Gravholt","year":"2001","unstructured":"Gravholt, C. H., Moller, N., Jensen, M. D., Christiansen, J. S. & Schmitz, O. Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis. J. Clin. Endocrinol. Metab. 86, 2085\u20132089 (2001).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"54080_CR45","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1007\/BF00257430","volume":"20","author":"SH Schneider","year":"1981","unstructured":"Schneider, S. H., Fineberg, S. E. & Blackburn, G. L. The acute metabolic effects of glucagon and its interactions with insulin in forearm tissue. Diabetologia 20, 616\u2013621 (1981).","journal-title":"Diabetologia"},{"key":"54080_CR46","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1007\/s00125-012-2803-y","volume":"56","author":"AM Arafat","year":"2013","unstructured":"Arafat, A. M. et al. Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis? Diabetologia 56, 588\u2013597 (2013).","journal-title":"Diabetologia"},{"key":"54080_CR47","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2019.110696","volume":"503","author":"MJ Pereira","year":"2020","unstructured":"Pereira, M. J. et al. Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes. Mol. Cell Endocrinol. 503, 110696 (2020).","journal-title":"Mol. Cell Endocrinol."},{"key":"54080_CR48","doi-asserted-by":"crossref","unstructured":"Nason, S. R. et al. Glucagon receptor signaling regulates weight loss via central KLB receptor complexes. JCI Insight 6, e141323 (2021).","DOI":"10.1172\/jci.insight.141323"},{"key":"54080_CR49","doi-asserted-by":"publisher","first-page":"3484","DOI":"10.1210\/en.2014-1175","volume":"155","author":"K Kinoshita","year":"2014","unstructured":"Kinoshita, K. et al. Glucagon is essential for adaptive thermogenesis in brown adipose tissue. Endocrinology 155, 3484\u20133492 (2014).","journal-title":"Endocrinology"},{"key":"54080_CR50","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.cmet.2016.07.023","volume":"24","author":"S Fabbiano","year":"2016","unstructured":"Fabbiano, S. et al. Caloric restriction leads to browning of white adipose tissue through type 2 immune signaling. Cell Metab. 24, 434\u2013446 (2016).","journal-title":"Cell Metab."},{"key":"54080_CR51","doi-asserted-by":"publisher","first-page":"3466","DOI":"10.1172\/JCI42845","volume":"120","author":"A Kosteli","year":"2010","unstructured":"Kosteli, A. et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J. Clin. Invest. 120, 3466\u20133479 (2010).","journal-title":"J. Clin. Invest."},{"key":"54080_CR52","doi-asserted-by":"publisher","first-page":"3508","DOI":"10.4049\/jimmunol.1200662","volume":"189","author":"G Zizzo","year":"2012","unstructured":"Zizzo, G., Hilliard, B. A., Monestier, M. & Cohen, P. L. Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J. Immunol. 189, 3508\u20133520 (2012).","journal-title":"J. Immunol."},{"key":"54080_CR53","doi-asserted-by":"crossref","unstructured":"Crespo, M. et al. Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism. Elife 9, e59258 (2020).","DOI":"10.7554\/eLife.59258"},{"key":"54080_CR54","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.2337\/db13-1440","volume":"63","author":"P Richards","year":"2014","unstructured":"Richards, P. et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63, 1224\u20131233 (2014).","journal-title":"Diabetes"},{"key":"54080_CR55","doi-asserted-by":"crossref","unstructured":"Welles, J. E., Dennis, M. D., Jefferson, L. S. & Kimball, S. R. Glucagon-dependent suppression of mTORC1 is associated with upregulation of hepatic FGF21 mRNA translation. Am. J. Physiol. Endocrinol. Metab. 319, E26\u2013E33 (2020).","DOI":"10.1152\/ajpendo.00555.2019"},{"key":"54080_CR56","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/j.cmet.2007.05.003","volume":"5","author":"T Inagaki","year":"2007","unstructured":"Inagaki, T. et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 5, 415\u2013425 (2007).","journal-title":"Cell Metab."},{"key":"54080_CR57","doi-asserted-by":"publisher","first-page":"4057","DOI":"10.2337\/db14-0595","volume":"63","author":"KR Markan","year":"2014","unstructured":"Markan, K. R. et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 63, 4057\u20134063 (2014).","journal-title":"Diabetes"},{"key":"54080_CR58","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.2337\/db12-1116","volume":"62","author":"KM Habegger","year":"2013","unstructured":"Habegger, K. M. et al. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62, 1453\u20131463 (2013).","journal-title":"Diabetes"},{"key":"54080_CR59","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/s41366-019-0433-x","volume":"44","author":"MA van Baak","year":"2020","unstructured":"van Baak, M. A. et al. Adipose tissue contribution to plasma fibroblast growth factor 21 and fibroblast activation protein in obesity. Int J. Obes. 44, 544\u2013547 (2020).","journal-title":"Int J. Obes."},{"key":"54080_CR60","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1146\/annurev-nutr-071816-064800","volume":"38","author":"LD BonDurant","year":"2018","unstructured":"BonDurant, L. D. & Potthoff, M. J. Fibroblast growth factor 21: a versatile regulator of metabolic homeostasis. Annu. Rev. Nutr. 38, 173\u2013196 (2018).","journal-title":"Annu. Rev. Nutr."},{"key":"54080_CR61","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/j.cmet.2016.01.006","volume":"23","author":"C Schlein","year":"2016","unstructured":"Schlein, C. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 23, 441\u2013453 (2016).","journal-title":"Cell Metab."},{"key":"54080_CR62","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1016\/j.cmet.2013.03.019","volume":"17","author":"WL Holland","year":"2013","unstructured":"Holland, W. L. et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 17, 790\u2013797 (2013).","journal-title":"Cell Metab."},{"key":"54080_CR63","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1016\/j.cmet.2017.09.004","volume":"26","author":"R Schreiber","year":"2017","unstructured":"Schreiber, R. et al. Cold-induced thermogenesis depends on ATGL-mediated lipolysis in cardiac muscle, but not brown adipose tissue. Cell Metab. 26, 753\u2013763.e757 (2017).","journal-title":"Cell Metab."},{"key":"54080_CR64","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.molmet.2019.01.011","volume":"22","author":"JL Beaudry","year":"2019","unstructured":"Beaudry, J. L. et al. The brown adipose tissue glucagon receptor is functional but not essential for control of energy homeostasis in mice. Mol. Metab. 22, 37\u201348 (2019).","journal-title":"Mol. Metab."},{"key":"54080_CR65","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.2337\/dc20-0460","volume":"43","author":"B Astiarraga","year":"2020","unstructured":"Astiarraga, B. et al. Impaired succinate response to a mixed meal in obesity and type 2 diabetes is normalized after metabolic surgery. Diabetes Care 43, 2581\u20132587 (2020).","journal-title":"Diabetes Care"},{"key":"54080_CR66","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-35869-4","volume":"8","author":"M Chodorge","year":"2018","unstructured":"Chodorge, M. et al. Engineering of a GLP-1 analogue peptide\/anti-PCSK9 antibody fusion for type 2 diabetes treatment. Sci. Rep. 8, 17545 (2018).","journal-title":"Sci. Rep."},{"key":"54080_CR67","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.molmet.2018.07.012","volume":"17","author":"B Rivero-Gutierrez","year":"2018","unstructured":"Rivero-Gutierrez, B. et al. Deletion of the glucagon receptor gene before and after experimental diabetes reveals differential protection from hyperglycemia. Mol. Metab. 17, 28\u201338 (2018).","journal-title":"Mol. Metab."},{"key":"54080_CR68","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1016\/0196-9781(89)90010-7","volume":"10","author":"CG Unson","year":"1989","unstructured":"Unson, C. G., Gurzenda, E. M. & Merrifield, R. B. Biological activities of des-His1[Glu9]glucagon amide, a glucagon antagonist. Peptides 10, 1171\u20131177 (1989).","journal-title":"Peptides"},{"key":"54080_CR69","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1677\/joe.1.05876","volume":"185","author":"BD Green","year":"2005","unstructured":"Green, B. D. et al. Chronic treatment with exendin(9-39)amide indicates a minor role for endogenous glucagon-like peptide-1 in metabolic abnormalities of obesity-related diabetes in ob\/ob mice. J. Endocrinol. 185, 307\u2013317 (2005).","journal-title":"J. Endocrinol."},{"key":"54080_CR70","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s00125-017-4491-0","volume":"61","author":"EK Biggs","year":"2018","unstructured":"Biggs, E. K. et al. Development and characterisation of a novel glucagon like peptide-1 receptor antibody. Diabetologia 61, 711\u2013721 (2018).","journal-title":"Diabetologia"},{"key":"54080_CR71","doi-asserted-by":"publisher","first-page":"e0120078","DOI":"10.1371\/journal.pone.0120078","volume":"10","author":"BJ Povinelli","year":"2015","unstructured":"Povinelli, B. J. et al. Standard sub-thermoneutral caging temperature influences radiosensitivity of hematopoietic stem and progenitor cells. PLoS ONE 10, e0120078 (2015).","journal-title":"PLoS ONE"},{"key":"54080_CR72","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1177\/2211068215587915","volume":"21","author":"J Naylor","year":"2016","unstructured":"Naylor, J., Rossi, A. & Hornigold, D. C. Acoustic dispensing preserves the potency of therapeutic peptides throughout the entire drug discovery workflow. J. Lab. Autom. 21, 90\u201396 (2016).","journal-title":"J. Lab. Autom."},{"key":"54080_CR73","doi-asserted-by":"publisher","first-page":"C83","DOI":"10.1152\/ajpcell.00246.2016","volume":"312","author":"S Perez-Diaz","year":"2017","unstructured":"Perez-Diaz, S. et al. Knockdown of PTRF ameliorates adipocyte differentiation and functionality of human mesenchymal stem cells. Am. J. Physiol. Cell Physiol. 312, C83\u2013C91 (2017).","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"54080_CR74","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s12575-009-9021-0","volume":"11","author":"JD Carter","year":"2009","unstructured":"Carter, J. D., Dula, S. B., Corbin, K. L., Wu, R. & Nunemaker, C. S. A practical guide to rodent islet isolation and assessment. Biol. Proced. Online 11, 3\u201331 (2009).","journal-title":"Biol. Proced. Online"},{"key":"54080_CR75","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.molmet.2017.10.008","volume":"7","author":"A Gonzalez-Rodriguez","year":"2018","unstructured":"Gonzalez-Rodriguez, A. et al. Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis. Mol. Metab. 7, 132\u2013146 (2018).","journal-title":"Mol. Metab."},{"key":"54080_CR76","doi-asserted-by":"publisher","first-page":"462","DOI":"10.2337\/diabetes.54.2.462","volume":"54","author":"L Herrero","year":"2005","unstructured":"Herrero, L. et al. Alteration of the malonyl-CoA\/carnitine palmitoyltransferase I interaction in the beta-cell impairs glucose-induced insulin secretion. Diabetes 54, 462\u2013471 (2005).","journal-title":"Diabetes"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54080-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54080-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54080-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T10:03:13Z","timestamp":1732788193000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-54080-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,28]]},"references-count":76,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["54080"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-54080-w","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,28]]},"assertion":[{"value":"7 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"D.H., C.M.R., L.J., J.F., and J.G. declare relationships with AstraZeneca (employee\/shareholder). The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10342"}}