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Adipose-specific Adss1 knockout increases energy expenditure and resistance to diet-induced obesity. Adss1 loss upregulates glycerol kinase, enhancing glycerol-dependent fatty acid re-esterification, reducing lipotoxic free fatty acids, and activating lipid cycling and thermogenic programs. Mechanistically, Adss1 alters HDAC3 nucleo-cytoplasmic distribution to boost Gk promoter acetylation.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/adenylosuccinate-synthase-1-deficiency-improves-energy-metabolism-by-promoting-adipose-tissue-re-esterification-via-glycerol-kinase-upregulation/439478/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/adenylosuccinate-synthase-1-deficiency-improves-energy-metabolism-by-promoting-adipose-tissue-re-esterification-via-glycerol-kinase-upregulation/439478.png","ImageObject",300,407,{"name":92,"@type":93},"Fahsai","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does Adss1 deficiency play in adipose energy metabolism?","Question",{"text":112,"@type":113},"Adss1 deficiency remodels inguinal white adipose tissue metabolism by promoting re-esterification processes that support energy expenditure and thermogenic programs.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does Adss1 deficiency affect glycerol kinase and lipid re-esterification?",{"text":117,"@type":113},"Loss of Adss1 upregulates glycerol kinase expression, stimulating glycerol-dependent fatty acid re-esterification in inguinal white adipose tissue.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links Adss1 to glycerol kinase regulation?",{"text":121,"@type":113},"Adss1 interacts with HDAC3 in beige adipocytes, changing HDAC3’s nucleo-cytoplasmic distribution. This suppresses HDAC activity and increases histone H3 lysine 27 acetylation at the Gk promoter, elevating glycerol kinase expression.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},439478,1790742769,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},549768702563,"https://ap-avatar.wpscdn.com/avatar/8000c4aa63b76e948b?x-image-process=image/resize,m_fixed,w_180,h_180&k=1786536092046926083","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nAdenylosuccinate Synthase 1 Deficiency Improves Energy Metabolism by Promoting Adipose Tissue Re-esterification via Glycerol Kinase Upregulation  \nJingjing Sun, Miriayi Alimujiang, Wenfei Li, Shuqin Chen, Yingying Su, Tingting Hu, Xuhong Lu, Yafen Ye, Ningning Bai, Fan Hu, Xiaoya Li, Rongrong Xu, Jun Xu, Jiarui Zhao, Yan Lu, Xiaojing Ma,* and Ying Yang*  \nPurine metabolism enzymes have a well-established role in maintaining the nucleotide pool, thereby sustaining cellular energy homeostasis. Although reduced purine nucleotide concentrations have been reported can influenceuncoupling protein 1 (UCP1)activity in thermogenic adipocytes, our study identifies adenylosuccinate synthase 1 (Adss1), an enzyme in de novo purine biosynthesis, as a critical regulator of metabolic remodeling in inguinal white adipose tissue (iWAT) through a mechanism distinct from UCP1 activity. Adipose-specific Adss1 knockout mice showed increased energy expenditure and resistance to diet-induced obesity with improved metabolic dysfunction. Loss ofAdss1 upregulates glycerol kinase (Gk) expression, thereby stimulating glycerol-dependent fatty acid re-esterification in iWAT. This adaptation prevents lipotoxic accumulation of free fatty acids and drives lipid synthesis–oxidation cycling, activating thermogenic programs. The Adss1 deficiency-driven iWAT browning and re-esterification are abolished in adipose-specific Adss1 and Gk double-knockout mice, confirming the functional dependence on Gk. Mechanistically, Adss1 interacts with histone deacetylase 3 (HDAC3) in the cytosol of beige adipocytes, altering its nucleo-cytoplasmic distribution. Adss1 deficiency reduced nuclear HDAC3 and increased cytosolic pools, which suppresses HDAC activity and enhances histone H3 lysine 27 acetylation at the Gk promoter, elevating Gk expression. Collectively, our findings reveal an unrecognized role of Adss1 in adipose physiology, highlighting its potential as a regulator of adipose energy metabolism.  \n1. Introduction  \nObesity results from an imbalance in energy homeostasis, characterized by energy intake exceeding energy expenditure. [1,2] White adipose tissue (WAT) plays a pivotal role in maintaining systemic energy balance by regulating lipid storage and mobilization,[3] as well as mediating the transformation of white adipocytes into beige adipocytes. [4] Under conditions of energy surplus, excess nutrients are stored as triglycerides (TG) in WAT.[3] However, excessive lipid accumulation can lead to lipotoxicity, causing adipose tissue dysfunction and subsequently contributing to metabolic disorders such as insulin resistance,[5,6] non-alcoholic fatty liver disease,[7] and metabolic cardiomyopathy.[8] Conversely, during periods of energy demand, such as fasting or exercise, TG in the WAT are broken down to produce non-esterified fatty acids (NEFA) and glycerol. These NEFA may be directly oxidized within adipocytesor exported as fuel for other tissues, such asthe liver and muscles. [9] Nonetheless, a significant proportion of NEFA is reabsorbed by adipocytes and re-esterified into TG, which, along with lipolysis, is referred to as  \nJ. Sun, M. Alimujiang, W. Li, Y. Su, T. Hu, X. Lu, Y. Ye, F. Hu, X. Li, R. Xu,  \nX. Ma, Y. Yang  \nDepartment of Endocrinology and Metabolism Shanghai Diabetes Institute  \nShanghai Clinical Center for Diabetes Shanghai Key Laboratory of Diabetes Mellitus  \nShanghai Key Clinical Center for Metabolic Disease  \nShanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  \nShanghai 200233, China  \n[E-mail:](E-mail: maxiaojing@sjtu.edu.cn)[ maxiaojing@sjtu.edu.cn](E-mail: maxiaojing@sjtu.edu.cn); [yangyingsh@sjtu.edu.cn](yangyingsh@sjtu.edu.cn)  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202506270](https://doi.org/10.1002/advs.202506270)[ ](https://doi.org/10.1002/advs.202506270)© 2","cbCaijjpnp1QOwdu","https://ap.wps.com/l/cbCaijjpnp1QOwdu","pdf",11310574,22,"English","# Introduction\n## Energy homeostasis and obesity mechanisms\n## Re-esterification (futile lipid cycle) and adipose browning\n## Purine metabolism and rationale for Adss1","[{\"question\":\"What role does Adss1 deficiency play in adipose energy metabolism?\",\"answer\":\"Adss1 deficiency remodels inguinal white adipose tissue metabolism by promoting re-esterification processes that support energy expenditure and thermogenic programs.\"},{\"question\":\"How does Adss1 deficiency affect glycerol kinase and lipid re-esterification?\",\"answer\":\"Loss of Adss1 upregulates glycerol kinase expression, stimulating glycerol-dependent fatty acid re-esterification in inguinal white adipose tissue.\"},{\"question\":\"What mechanism links Adss1 to glycerol kinase regulation?\",\"answer\":\"Adss1 interacts with HDAC3 in beige adipocytes, changing HDAC3’s nucleo-cytoplasmic distribution. This suppresses HDAC activity and increases histone H3 lysine 27 acetylation at the Gk promoter, elevating glycerol kinase expression.\"}]","Adenylosuccinate Synthase 1 Deficiency Improves Energy Metabolism by Promoting Adipose Tissue Re-esterification via Glycerol Kinase Upregulation | PDF",1790688852,55]