The Gly482Ser PPARGC1A polymorphism regulates PGC-1α stability and human brown adipocyte mitochondrial function under cold exposure

The Gly482Ser PPARGC1A polymorphism regulates PGC-1α stability and human brown adipocyte mitochondrial function under cold exposure | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Gly482Ser PPARGC1A polymorphism regulates PGC-1α stability and human brown adipocyte mitochondrial function under cold exposure Sebastian Kalamajski, Mi Huang, Shandilya Baira, Daniel Coral, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5219205/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Adaptive thermogenesis in brown adipose tissue is regulated by PPARGC1A (PGC-1α), which could be affected by common polymorphism (rs8192678, Gly482Ser) that associates with metabolic disorders. We used CRISPR-Cas9 in immortalized human brown adipocyte cell line to edit the rs8192678 locus to evaluate the allele-dependent effects on cold response of brown adipocytes. In both 482Ser- and 482Gly-edited brown adipocytes, UCP1 expression increased after 6-hour cold exposure, but the increase was less pronounced in 482Gly cells, which also had lower mitochondrial activity. Furthermore, 482Gly PGC-1α had an almost two-fold longer half-life at 37°C, and four-fold longer half-life at 32°C, compared with the 482Ser variant. Despite the longer half-life, the 482Gly PGC-1α had lower activity, and was more prone to be retained in the cytoplasm after cold exposure. Our experimental data support gene x environment interactions between Gly482Ser and cold exposure in human brown adipocytes. These data support a novel molecular basis for the epidemiological observations that link the Gly482Ser polymorphism with obesity and related metabolic disorders. Biological sciences/Genetics/Functional genomics Biological sciences/Cell biology/Mechanisms of disease Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5219205","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":365967922,"identity":"605291a1-2af0-43c6-b6d3-482184bd7502","order_by":0,"name":"Sebastian Kalamajski","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-6600-9302","institution":"Lund University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"","lastName":"Kalamajski","suffix":""},{"id":365967923,"identity":"d0a6f9f4-3a23-4800-9440-792f69ae7c53","order_by":1,"name":"Mi Huang","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mi","middleName":"","lastName":"Huang","suffix":""},{"id":365967924,"identity":"cc065a6e-2314-41c8-8ec9-612b07a9e56d","order_by":2,"name":"Shandilya Baira","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shandilya","middleName":"","lastName":"Baira","suffix":""},{"id":365967925,"identity":"bea7dfc0-dd28-4137-ba22-aa58b07a83eb","order_by":3,"name":"Daniel Coral","email":"","orcid":"https://orcid.org/0000-0002-8809-4544","institution":"Lund University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Coral","suffix":""},{"id":365967926,"identity":"87fd62bd-2708-458a-afc1-2eb2684cf6c6","order_by":4,"name":"Peter Spégel","email":"","orcid":"https://orcid.org/0000-0002-6092-2387","institution":"Lund University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Spégel","suffix":""},{"id":365967927,"identity":"3c3ce64b-c6a3-477e-b9e7-70b2748de9a0","order_by":5,"name":"Melina Claussnitzer","email":"","orcid":"https://orcid.org/0000-0003-2450-736X","institution":"Massachusetts General Hospital, Harvard Medical School; Type 2 Diabetes Systems Genomics, Broad Institute of MIT and Harvard, Initiative, Cambridge MA","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Melina","middleName":"","lastName":"Claussnitzer","suffix":""},{"id":365967928,"identity":"0fe96517-ca7a-450f-8086-1cc3803f074c","order_by":6,"name":"Hindrik Mulder","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hindrik","middleName":"","lastName":"Mulder","suffix":""},{"id":365967929,"identity":"ce7cd120-ef22-4377-96ed-bb45d7d34506","order_by":7,"name":"Paul Franks","email":"","orcid":"https://orcid.org/0000-0002-0520-7604","institution":"Lund University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"Franks","suffix":""}],"badges":[],"createdAt":"2024-10-07 15:10:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5219205/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5219205/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":70479540,"identity":"04ff56d9-6bf1-44bb-8c46-176480548eda","added_by":"auto","created_at":"2024-12-03 14:46:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2576306,"visible":true,"origin":"","legend":"Article File","description":"","filename":"rs8192678manuscriptcomplete.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5219205/v1_covered_1f2abcb7-7859-4702-91ee-08e6079964e0.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"The Gly482Ser PPARGC1A polymorphism regulates PGC-1α stability and human brown adipocyte mitochondrial function under cold exposure","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5219205/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5219205/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Adaptive thermogenesis in brown adipose tissue is regulated by PPARGC1A (PGC-1α), which could be affected by common polymorphism (rs8192678, Gly482Ser) that associates with metabolic disorders. We used CRISPR-Cas9 in immortalized human brown adipocyte cell line to edit the rs8192678 locus to evaluate the allele-dependent effects on cold response of brown adipocytes. In both 482Ser- and 482Gly-edited brown adipocytes, UCP1 expression increased after 6-hour cold exposure, but the increase was less pronounced in 482Gly cells, which also had lower mitochondrial activity. Furthermore, 482Gly PGC-1α had an almost two-fold longer half-life at 37°C, and four-fold longer half-life at 32°C, compared with the 482Ser variant. Despite the longer half-life, the 482Gly PGC-1α had lower activity, and was more prone to be retained in the cytoplasm after cold exposure. Our experimental data support gene x environment interactions between Gly482Ser and cold exposure in human brown adipocytes. These data support a novel molecular basis for the epidemiological observations that link the Gly482Ser polymorphism with obesity and related metabolic disorders.","manuscriptTitle":"The Gly482Ser PPARGC1A polymorphism regulates PGC-1α stability and human brown adipocyte mitochondrial function under cold exposure","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-03 14:38:04","doi":"10.21203/rs.3.rs-5219205/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-biology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsbio","sideBox":"Learn more about [Communications Biology](http://www.nature.com/commsbio/)","snPcode":"","submissionUrl":"","title":"Communications Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6e636433-6b62-416f-85ac-88995c929a42","owner":[],"postedDate":"December 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":38932611,"name":"Biological sciences/Genetics/Functional genomics"},{"id":38932612,"name":"Biological sciences/Cell biology/Mechanisms of disease"}],"tags":[],"updatedAt":"2024-12-03T14:38:04+00:00","versionOfRecord":[],"versionCreatedAt":"2024-12-03 14:38:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5219205","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5219205","identity":"rs-5219205","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}