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The underlying mechanisms are undetermined, and no therapy is available. We experimentally investigated whether pharmacologically targeting obesity, which is highly prevalent in type 2 diabetes, before stroke enhances neurological recovery in type 2 diabetes. To induce weight loss, we employed the glucagon-like peptide\u00a01 receptor (GLP-1R) agonist semaglutide and the neuropeptide\u00a0Y receptor Y2 (NPY2R) agonist BI8271, which potentiates GLP-1R-mediated weight loss. We also investigated potential acute neuroprotective effects induced by these treatments, independently of metabolic regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>C57BL\/6J mice were fed with a high-fat diet for 5 months to induce obesity and features of type 2 diabetes (i.e. hyperglycaemia and insulin resistance). Weight loss was induced by 4-week administration of semaglutide and\/or BI8271. As a control for the effect of weight loss, a vehicle (PBS)-treated group was switched to standard diet to achieve the same weight range and the same percentage weight loss within the same time frame as those receiving semaglutide\/BI8271. Thereafter, mice were subjected to stroke by transient middle cerebral artery occlusion (tMCAO). Stroke recovery (the primary outcome) was assessed by measuring the recovery of grip strength and the lateralised sensorimotor integration. Brains and serum were collected, and stroke volume and serum IGF-1 levels were quantified (secondary outcomes). In additional studies, type 2 diabetic mice were subjected to tMCAO and injected with semaglutide and\/or BI8271 1 and 24\u00a0h after reperfusion. Acute neuroprotection (the primary outcome) was assessed by a grip strength test and by quantifying stroke volume and the number of surviving neuronal nuclear marker (NeuN)-positive neurons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We report that pre-stroke weight loss by GLP-1R activation, and more potently by dual co-activation of GLP-1 and NPY2 receptors, is a pharmacologically targetable mechanism, upstream of glycaemic regulation, through which post-stroke recovery is achieved. Moreover, we show that post-stroke recovery in type 2 diabetes is inversely associated with peripheral IGF-1 levels. Finally, GLP-1R and NPY2R activation can also improve stroke recovery through acute neuroprotection if they are given acutely after stroke, independently of their metabolic effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>The diabetes and obesity epidemics are increasing the incidence of stroke, and consequently the need for treatments to improve stroke outcome. Our results indicate that clinically used type 2 diabetes treatments could be employed in a preventive role to improve stroke outcome by exerting dual pharmacological action: weight loss and acute neuroprotection. These findings could have novel therapeutic implications for many people.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-025-06567-4","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T20:27:05Z","timestamp":1760560025000},"page":"230-243","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pre-stroke weight loss by glucagon-like peptide\u00a01 receptor and neuropeptide\u00a0Y receptor Y2 activation improves post-stroke functional recovery in male diabetic mouse models"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9425-4209","authenticated-orcid":false,"given":"Ellen","family":"Vercalsteren","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5316-088X","authenticated-orcid":false,"given":"Dimitra","family":"Karampatsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Neicu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4719-6624","authenticated-orcid":false,"given":"Mihaela Oana","family":"Romanitan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5861-9613","authenticated-orcid":false,"given":"Peter","family":"Haebel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6269-1061","authenticated-orcid":false,"given":"Katherin","family":"Bleymehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3462-7990","authenticated-orcid":false,"given":"Thomas","family":"Nystr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5762-9166","authenticated-orcid":false,"given":"Thomas","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6693-934X","authenticated-orcid":false,"given":"Vladimer","family":"Darsalia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0470-4606","authenticated-orcid":false,"given":"Cesare","family":"Patrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"issue":"10394","key":"6567_CR1","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1016\/S0140-6736(23)01296-5","volume":"401","author":"The Lancet","year":"2023","unstructured":"The Lancet (2023) Diabetes: a defining disease of the 21st century. 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Bahram (Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden) for technical assistance, and H. Pettersson (Department of Clinical Science and Education, Karolinska Institutet, Stockholm, Sweden) for advice on statistical analyses.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The data that support the findings of this study are not openly available for reasons of sensitivity, but are available from the corresponding author upon reasonable request. Data are located in controlled-access data storage (data repository) at the Karolinska Institutet.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Open access funding provided by Karolinska Institute. Funding was provided by the Swedish Medical Research Council (to CP), the FANG Foundation and the Swedish Brain Foundation (to CP), the Swedish Heart\u2013Lung Foundation (to TN), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse (to TN), the Ulla Hamberg Angeby och Lennart Angebys Stiftelse (to VD and EV), the Swedish Stroke Foundation (to CP, VD and EV), the Foundation for Geriatric Diseases at Karolinska Institutet (to EV), ALF Stockholm (to TN) and by a grant from Boehringer Ingelheim Pharma GmbH & Co. KG.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"TN has received consultancy fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Merck and Sanofi. TK, PH and KB are employed at Boehringer Ingelheim Pharma GmbH & Co. KG. The remaining authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"EV substantially contributed to the design of the work, performed part of the drug administration and diabetic tests in studies 1\u20133, and part of the immunohistochemical and stereology analysis. Moreover, she drafted and critically reviewed the article with DK, and approved the final version of the manuscript. DK substantially contributed to the design of the work, performed part of the drug administration and diabetic tests in studies 1 and 3 and part of the immunohistochemical and stereology analysis, and acquired\/processed images. Moreover, she drafted and critically reviewed the article with EV, and approved the final version of the manuscript. MN performed part of the immunohistochemical studies and reviewed the article critically. MOR provided resources and contributed to the conception of the work. She also reviewed the manuscript. TN contributed to the conception of the study, provided resources, and critically revised the manuscript. PH synthesised the BI8271 compound and substantially contributed to the analysis and interpretation of data and critically reviewed the article. KB provided the data used to determine the doses of the compounds, contributed to the analysis and interpretation of data and critically reviewed the article. TK conceived the study and provided resources, including semaglutide\/BI8271, and revised the manuscript. VD conceived and designed the study, performed the stroke experiments and part of the diabetic\/functional tests, and edited the manuscript. CP conceived, designed and coordinated the research plan, and wrote the manuscript. All authors approved the final version to be published. EV, VD and CP are responsible for the integrity of the work as a whole.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}