Background and purpose: Seipin, which regulates adipocyte differentiation and lipolysis, inducing severe lipodystrophy and metabolic syndromes, is also highly expressed in the nervous system and affects some neurological diseases. However, the impacts of seipin in stroke remain unclear. Methods and results: In this study, we subjected seipin knockout mice to cerebral ischemia/reperfusion injury and found that seipin knockout mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by blood-brain barrier (BBB) damages. Furthermore, we showed that seipin knockout aggravated endoplasmic reticulum (ER) stress and significantly increased glucose levels, decreased leptin and adiponectin levels in mouse plasma. Conclusions: Our findings reveal that seipin knockout exacerbates cerebral I/R-induced damages by increasing BBB permeability, amplifying ER stress and increasing glucose levels, as well as decreasing leptin and adiponectin levels, indicating that seipin may be a potential therapeutic target for stroke. (C) 2016 Elsevier Inc. All rights reserved.