{"id":"https://openalex.org/W7224888203","doi":"https://doi.org/10.21203/rs.3.rs-11471586/v1","title":"High glucose promotes PRDM16 proteolysis and adipose tissue fibrosis","display_name":"High glucose promotes PRDM16 proteolysis and adipose tissue fibrosis","publication_year":2026,"publication_date":"2026-10-30","ids":{"openalex":"https://openalex.org/W7224888203","doi":"https://doi.org/10.21203/rs.3.rs-11471586/v1","pmid":"https://pubmed.ncbi.nlm.nih.gov/42990537","pmcid":"https://www.ncbi.nlm.nih.gov/pmc/articles/13734277"},"language":"en","primary_location":{"id":"doi:10.21203/rs.3.rs-11471586/v1","doi":"https://doi.org/10.21203/rs.3.rs-11471586/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-11471586/v1","pdf_url":"https://www.researchsquare.com/article/rs-11471586/latest.pdf","source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},"volume":null,"type":"preprint","is_traditional":true,"indexed_in":["crossref","pubmed"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://www.researchsquare.com/article/rs-11471586/latest.pdf","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5091039728","display_name":"Shingo Kajimura","orcid":"https://orcid.org/0000-0003-0672-5910","observed_orcids":["https://orcid.org/0000-0003-0672-5910"]},"institutions":[{"id":"https://openalex.org/I1316535847","display_name":"Beth Israel Deaconess Medical Center","ror":"https://ror.org/04drvxt59","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1316535847"]},{"id":"https://openalex.org/I1344073410","display_name":"Howard Hughes Medical Institute","ror":"https://ror.org/006w34k90","country_code":"US","type":"facility","lineage":["https://openalex.org/I1344073410"]},{"id":"https://openalex.org/I136199984","display_name":"Harvard University","ror":"https://ror.org/03vek6s52","country_code":"US","type":"education","lineage":["https://openalex.org/I136199984"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Shingo Kajimura","raw_affiliation_strings":["Beth Israel Deaconess Medical Center, Harvard Medical School, and Howard Hughes Medical Institute"],"raw_orcid":"https://orcid.org/0000-0003-0672-5910","affiliations":[{"raw_affiliation_string":"Beth Israel Deaconess Medical Center, Harvard Medical School, and Howard Hughes Medical Institute","institution_ids":["https://openalex.org/I1316535847","https://openalex.org/I1344073410","https://openalex.org/I136199984"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5007568196","display_name":"Yong Chen","orcid":"https://orcid.org/0000-0002-0723-8105","observed_orcids":["https://orcid.org/0000-0002-0723-8105"]},"institutions":[{"id":"https://openalex.org/I37461747","display_name":"Wuhan University","ror":"https://ror.org/033vjfk17","country_code":"CN","type":"education","lineage":["https://openalex.org/I37461747"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Yong Chen","raw_affiliation_strings":["Wuhan University"],"raw_orcid":"https://orcid.org/0000-0002-0723-8105","affiliations":[{"raw_affiliation_string":"Wuhan University","institution_ids":["https://openalex.org/I37461747"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5100379355","display_name":"Li Chen","orcid":"https://orcid.org/0000-0003-3988-5865","observed_orcids":["https://orcid.org/0000-0003-3988-5865"]},"institutions":[{"id":"https://openalex.org/I1316535847","display_name":"Beth Israel Deaconess Medical Center","ror":"https://ror.org/04drvxt59","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1316535847"]},{"id":"https://openalex.org/I136199984","display_name":"Harvard University","ror":"https://ror.org/03vek6s52","country_code":"US","type":"education","lineage":["https://openalex.org/I136199984"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Li Chen","raw_affiliation_strings":["Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School","institution_ids":["https://openalex.org/I1316535847","https://openalex.org/I136199984"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5129713437","display_name":"Yusuke Higuchi","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I1316535847","display_name":"Beth Israel Deaconess Medical Center","ror":"https://ror.org/04drvxt59","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1316535847"]},{"id":"https://openalex.org/I1344073410","display_name":"Howard Hughes Medical Institute","ror":"https://ror.org/006w34k90","country_code":"US","type":"facility","lineage":["https://openalex.org/I1344073410"]},{"id":"https://openalex.org/I136199984","display_name":"Harvard University","ror":"https://ror.org/03vek6s52","country_code":"US","type":"education","lineage":["https://openalex.org/I136199984"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Yusuke Higuchi","raw_affiliation_strings":["Beth Israel Deaconess Medical Center, Harvard Medical School, and Howard Hughes Medical Institute"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Beth Israel Deaconess Medical Center, Harvard Medical School, and Howard Hughes Medical Institute","institution_ids":["https://openalex.org/I1316535847","https://openalex.org/I1344073410","https://openalex.org/I136199984"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5021792801","display_name":"Daisuke Kato","orcid":"https://orcid.org/0000-0002-8168-8841","observed_orcids":["https://orcid.org/0000-0002-8168-8841"]},"institutions":[{"id":"https://openalex.org/I1316535847","display_name":"Beth Israel Deaconess Medical Center","ror":"https://ror.org/04drvxt59","country_code":"US","type":"healthcare","lineage":["https://openalex.org/I1316535847"]},{"id":"https://openalex.org/I1344073410","display_name":"Howard Hughes Medical Institute","ror":"https://ror.org/006w34k90","country_code":"US","type":"facility","lineage":["https://openalex.org/I1344073410"]},{"id":"https://openalex.org/I136199984","display_name":"Harvard University","ror":"https://ror.org/03vek6s52","country_code":"US","type":"education","lineage":["https://openalex.org/I136199984"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Daisuke Kato","raw_affiliation_strings":["Beth Israel Deaconess Medical Center, Harvard Medical School, and Howard Hughes Medical Institute"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Beth Israel Deaconess Medical Center, Harvard Medical School, and Howard Hughes Medical Institute","institution_ids":["https://openalex.org/I1316535847","https://openalex.org/I1344073410","https://openalex.org/I136199984"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5160166341","display_name":"Qiang Wang","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I99065089","display_name":"Tsinghua University","ror":"https://ror.org/03cve4549","country_code":"CN","type":"education","lineage":["https://openalex.org/I99065089"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Qiang Wang","raw_affiliation_strings":["Tsinghua University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Tsinghua University","institution_ids":["https://openalex.org/I99065089"]}]}],"institutions":[],"countries_distinct_count":2,"institutions_distinct_count":5,"corresponding_author_ids":[],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11457","display_name":"Adipose Tissue and Metabolism","score":0.5541999936103821,"subfield":{"id":"https://openalex.org/subfields/2737","display_name":"Physiology (medical)"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T11457","display_name":"Adipose Tissue and Metabolism","score":0.5541999936103821,"subfield":{"id":"https://openalex.org/subfields/2737","display_name":"Physiology (medical)"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10528","display_name":"Adipokines, Inflammation, and Metabolic Diseases","score":0.42989999055862427,"subfield":{"id":"https://openalex.org/subfields/2712","display_name":"Endocrinology, Diabetes and Metabolism"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T11072","display_name":"Peroxisome Proliferator-Activated Receptors","score":0.003599999938160181,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/prdm16","display_name":"PRDM16","score":0.8529999852180481},{"id":"https://openalex.org/keywords/o-glcnacylation","display_name":"O-GlcNAcylation","score":0.9890000224113464},{"id":"https://openalex.org/keywords/adipose-tissue-fibrosis","display_name":"adipose tissue fibrosis","score":0.8399999737739563},{"id":"https://openalex.org/keywords/hyperglycemia","display_name":"hyperglycemia","score":0.8899999856948853},{"id":"https://openalex.org/keywords/ubiquitination","display_name":"ubiquitination","score":0.7720000147819519},{"id":"https://openalex.org/keywords/proteasomal-degradation","display_name":"proteasomal degradation","score":0.9779999852180481},{"id":"https://openalex.org/keywords/insulin-resistance","display_name":"insulin resistance","score":0.8259999752044678},{"id":"https://openalex.org/keywords/type-2-diabetes","display_name":"type 2 diabetes","score":0.9789999723434448},{"id":"https://openalex.org/keywords/glucose-homeostasis","display_name":"glucose homeostasis","score":0.6819999814033508},{"id":"https://openalex.org/keywords/adipose-tissue-inflammation","display_name":"adipose tissue inflammation","score":0.7630000114440918},{"id":"https://openalex.org/keywords/post-translational-regulation","display_name":"post-translational regulation","score":0.8410000205039978}],"concepts":[{"id":"https://openalex.org/C143128242","wikidata":"https://www.wikidata.org/wiki/Q18045527","display_name":"PRDM16","level":4,"score":0.8884999752044678},{"id":"https://openalex.org/C171089720","wikidata":"https://www.wikidata.org/wiki/Q193583","display_name":"Adipose tissue","level":2,"score":0.8500999808311462},{"id":"https://openalex.org/C126322002","wikidata":"https://www.wikidata.org/wiki/Q11180","display_name":"Internal medicine","level":1,"score":0.6747000217437744},{"id":"https://openalex.org/C134018914","wikidata":"https://www.wikidata.org/wiki/Q162606","display_name":"Endocrinology","level":1,"score":0.6654999852180481},{"id":"https://openalex.org/C2777391703","wikidata":"https://www.wikidata.org/wiki/Q1053470","display_name":"Insulin resistance","level":3,"score":0.5852000117301941},{"id":"https://openalex.org/C2781307694","wikidata":"https://www.wikidata.org/wiki/Q33123","display_name":"Proteolysis","level":3,"score":0.5271000266075134},{"id":"https://openalex.org/C151955695","wikidata":"https://www.wikidata.org/wiki/Q654528","display_name":"White adipose tissue","level":3,"score":0.4977000057697296},{"id":"https://openalex.org/C17675752","wikidata":"https://www.wikidata.org/wiki/Q12898553","display_name":"Adipose tissue macrophages","level":4,"score":0.45509999990463257},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.45500001311302185},{"id":"https://openalex.org/C2779306644","wikidata":"https://www.wikidata.org/wiki/Q2002370","display_name":"Insulin","level":2,"score":0.4271000027656555},{"id":"https://openalex.org/C2780559512","wikidata":"https://www.wikidata.org/wiki/Q605709","display_name":"Fibrosis","level":2,"score":0.4065000116825104},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.3901999890804291},{"id":"https://openalex.org/C25602115","wikidata":"https://www.wikidata.org/wiki/Q407111","display_name":"Ubiquitin","level":3,"score":0.37310001254081726},{"id":"https://openalex.org/C2780642333","wikidata":"https://www.wikidata.org/wiki/Q901269","display_name":"Brown adipose tissue","level":3,"score":0.3668000102043152},{"id":"https://openalex.org/C134459356","wikidata":"https://www.wikidata.org/wiki/Q4274835","display_name":"Ubiquitin ligase","level":4,"score":0.3562000095844269},{"id":"https://openalex.org/C106646824","wikidata":"https://www.wikidata.org/wiki/Q5425475","display_name":"FGF21","level":4,"score":0.35260000824928284},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.328900009393692},{"id":"https://openalex.org/C201624660","wikidata":"https://www.wikidata.org/wiki/Q15334084","display_name":"IRS1","level":5,"score":0.3059999942779541},{"id":"https://openalex.org/C2777866211","wikidata":"https://www.wikidata.org/wiki/Q5572349","display_name":"Glucose uptake","level":3,"score":0.304500013589859},{"id":"https://openalex.org/C112446052","wikidata":"https://www.wikidata.org/wiki/Q422579","display_name":"Insulin receptor","level":4,"score":0.2946000099182129},{"id":"https://openalex.org/C6929976","wikidata":"https://www.wikidata.org/wiki/Q3771881","display_name":"Regulator","level":3,"score":0.2904999852180481},{"id":"https://openalex.org/C151279926","wikidata":"https://www.wikidata.org/wiki/Q965695","display_name":"Thermogenesis","level":3,"score":0.2825999855995178},{"id":"https://openalex.org/C127561419","wikidata":"https://www.wikidata.org/wiki/Q224527","display_name":"Downregulation and upregulation","level":3,"score":0.27230000495910645},{"id":"https://openalex.org/C195580219","wikidata":"https://www.wikidata.org/wiki/Q7251511","display_name":"Protein turnover","level":3,"score":0.26989999413490295},{"id":"https://openalex.org/C183786373","wikidata":"https://www.wikidata.org/wiki/Q5964993","display_name":"Signal transducing adaptor protein","level":3,"score":0.251800000667572},{"id":"https://openalex.org/C2992195973","wikidata":"https://www.wikidata.org/wiki/Q33123","display_name":"Protein degradation","level":2,"score":0.2515999972820282}],"mesh":[],"locations_count":2,"locations":[{"id":"doi:10.21203/rs.3.rs-11471586/v1","doi":"https://doi.org/10.21203/rs.3.rs-11471586/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-11471586/v1","pdf_url":"https://www.researchsquare.com/article/rs-11471586/latest.pdf","source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},{"id":"pmid:42990537","doi":null,"is_oa":false,"landing_page_url":"https://pubmed.ncbi.nlm.nih.gov/42990537","pdf_url":null,"source":{"id":"https://openalex.org/S4306525036","display_name":"PubMed","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I1299303238","host_organization_name":"National Institutes of Health","host_organization_lineage":["https://openalex.org/I1299303238"],"host_organization_lineage_names":[],"type":"repository"},"license":null,"license_id":null,"version":"publishedVersion","is_accepted":true,"is_published":true,"raw_source_name":"Research square","raw_type":"Journal Article"}],"best_oa_location":{"id":"doi:10.21203/rs.3.rs-11471586/v1","doi":"https://doi.org/10.21203/rs.3.rs-11471586/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-11471586/v1","pdf_url":"https://www.researchsquare.com/article/rs-11471586/latest.pdf","source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},"sustainable_development_goals":[{"display_name":"Good health and well-being","score":0.9763000011444092,"id":"https://metadata.un.org/sdg/3"}],"study_designs":[],"awards":[],"funders":[],"has_content":{"pdf":true,"grobid_xml":true},"content_urls":{"pdf":"https://content.openalex.org/works/W7224888203.pdf","grobid_xml":"https://content.openalex.org/works/W7224888203.grobid-xml"},"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W2783764158","https://openalex.org/W4377967630","https://openalex.org/W4294636786","https://openalex.org/W4225689590","https://openalex.org/W4392857287","https://openalex.org/W4399690673","https://openalex.org/W2025681262","https://openalex.org/W4412088421","https://openalex.org/W2295964029","https://openalex.org/W2808717970"],"abstract_inverted_index":{"Abstract":[0],"Chronic":[1],"nutrient":[2,160],"excess":[3,161],"drives":[4],"adipose":[5,31,54,123,163],"tissue":[6,32,55,124,164],"fibrosis":[7],"and":[8,19,87,118,129],"inflammation,":[9,126],"key":[10,50],"features":[11],"of":[12,53,59,75,115,137,143,169],"metabolic":[13,133,141],"dysfunction":[14,165],"that":[15,158],"underlie":[16],"insulin":[17,130],"resistance":[18],"Type":[20],"2":[21,71],"diabetes.":[22],"However,":[23],"the":[24,147],"molecular":[25],"mechanisms":[26],"linking":[27],"hyperglycemia":[28],"to":[29,162],"pathological":[30],"remodeling":[33],"remain":[34],"less":[35],"understood.":[36],"Here,":[37],"we":[38],"identify":[39],"a":[40,49,93,154],"post-translational":[41,167],"mechanism":[42],"by":[43],"which":[44],"high":[45],"glucose":[46,103,127],"destabilizes":[47],"PRDM16,":[48,83],"transcriptional":[51],"regulator":[52],"identity,":[56],"through":[57,166],"O-GlcNAcylation":[58,74],"its":[60,80],"E3":[61],"ligase":[62],"adaptor":[63],"protein,":[64],"amyloid":[65],"beta":[66],"precursor":[67],"protein":[68,70,112,171],"binding":[69],"(APPBP2).":[72],"Glucose-induced":[73],"APPBP2":[76],"at":[77],"S561":[78],"promotes":[79],"interaction":[81],"with":[82],"triggering":[84],"PRDM16":[85,111,170],"ubiquitination":[86],"proteasomal":[88],"degradation.":[89],"Notably,":[90],"APPBP2S561N":[91,108,144],"is":[92],"hypomorphic":[94],"variant":[95],"identified":[96],"in":[97,146],"human":[98],"populations":[99],"who":[100],"exhibit":[101],"improved":[102],"homeostasis.":[104],"Knock-in":[105],"mice":[106],"harboring":[107],"maintained":[109],"elevated":[110],"levels":[113],"independently":[114],"mRNA":[116],"abundance":[117],"are":[119,135],"protected":[120],"against":[121],"diet-induced":[122],"fibrosis,":[125],"intolerance,":[128],"resistance.":[131],"These":[132,151],"benefits":[134],"independent":[136],"UCP1-mediated":[138],"thermogenesis,":[139],"as":[140],"protection":[142],"persists":[145],"Ucp1":[148],"null":[149],"background.":[150],"findings":[152],"reveal":[153],"glucose-responsive":[155],"O-GlcNAc":[156],"pathway":[157],"couples":[159],"regulation":[168],"stability.":[172]},"counts_by_year":[],"updated_date":"2026-11-07T11:25:07.637180","created_date":"2026-10-31T00:00:00"}