Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson’s disease

Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson’s disease | 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 Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson’s disease K.C. Biju, Enrique Hernandez, Alison Stallings, Ada Felix-Ortiz, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4870881/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Apr, 2025 Read the published version in npj Parkinson's Disease → Version 1 posted 10 You are reading this latest preprint version Abstract Unintentional weight loss, primarily due to the loss of fat mass rather than muscle mass, is common among patients with Parkinson’s disease (PD) and is associated with poor quality of life and accelerated disease progression. Since transgenic mice overexpressing human wild-type α-synuclein (α-Syn mice) are modestly leaner than control mice, and since diabetes, a metabolic disorder, is a major risk factor for PD, we reasoned that high-fat diet-induced diabetes/metabolic dysregulation in α-Syn mice may serve as a robust tool for exploring how early α-synuclein pathology contributes to metabolic dysregulation, leading to weight loss in PD. Thus, α-Syn and age-matched controls were fed a high-fat diet (HFD) chow (60% fat calories) ad libitum for four months. Compared with controls on HFD (control-HFD), α-Syn mice on HFD (α-Syn-HFD) were dramatically leaner. The resistance to gaining weight in α-Syn-HFD mice was accompanied by improved glucose tolerance, a dramatic decrease in fat mass, and an increase in energy expenditure. Despite this leaner phenotype and better glucose tolerance, the mortality was much higher in male α-Syn-HFD mice than in all controls, but was unaffected in females, suggesting protective effects of female sex hormones, as well as lower α-synuclein levels. Immunoblot analysis of insulin signaling in the olfactory bulb, the proposed initial seeding site of α-synuclein pathology, revealed a decrease of IGF-IRβ, p GSK, and p mTOR in α-Syn-HFD mice. Since GSK-3β and mTOR regulate synaptic plasticity, we assessed levels of PSD-95 and synaptophysin in the olfactory bulb. As anticipated, we observed a significant decrease in the levels of PSD-95, along with a potentially compensatory increase in synaptophysin levels. Our results show that α-Syn mice, when challenged with diet-induced diabetes/metabolic dysregulation, clearly reveal a profile of robust metabolic dysfunction, thus providing a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. We propose a role for olfactory dysfunction in PD-related unintentional weight loss and suggest that strategies aimed at increasing body weight/BMI will improve the quality of life and prognosis for people living with PD. Biological sciences/Neuroscience/Diseases of the nervous system/Parkinson's disease Biological sciences/Neuroscience/Olfactory system Full Text Additional Declarations (Not answered) Cite Share Download PDF Status: Published Journal Publication published 24 Apr, 2025 Read the published version in npj Parkinson's Disease → Version 1 posted Editorial decision: revise 14 Oct, 2024 Review # 3 received at journal 01 Sep, 2024 Reviewer # 3 agreed at journal 24 Aug, 2024 Review # 1 received at journal 22 Aug, 2024 Reviewer # 2 agreed at journal 19 Aug, 2024 Reviewer # 1 agreed at journal 08 Aug, 2024 Reviewers invited by journal 07 Aug, 2024 Editor assigned by journal 07 Aug, 2024 Submission checks completed at journal 07 Aug, 2024 First submitted to journal 06 Aug, 2024 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-4870881","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":337355546,"identity":"13f4136c-fa73-4b52-8d6b-e896ae59c837","order_by":0,"name":"K.C. Biju","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAw0lEQVRIiWNgGAWjYDACCSDmYbCBMMDgAHFa0hh4SNVymAQt/LObnz1423Y+cb90+8OPP2oY5PhuJBCw5M4xc8O5bbcTe2TOGEvzHGMwliSkxUAiwUyaF6RFIoeNmYGNIXEDYS3p34BazgG1pD9j/PGPoZ4ILTkgWw4AtSSYMfC2MSQYEPTLjZwyyTnnko17buQYS/P2SRjOPPMAvxb+GenbJN6U2cm2z0gHhtg3G3m+4wRswbCVNOWjYBSMglEwCrADAIGjQrTsIyrjAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8409-6374","institution":"The University of Texas Health Science Center at San Antonio","correspondingAuthor":true,"prefix":"","firstName":"K.C.","middleName":"","lastName":"Biju","suffix":""},{"id":337355547,"identity":"77f1c4fa-d76b-435c-a8f0-dfd7877d390e","order_by":1,"name":"Enrique Hernandez","email":"","orcid":"","institution":"The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Enrique","middleName":"","lastName":"Hernandez","suffix":""},{"id":337355548,"identity":"9f3d3c29-346c-4017-a7cc-2bea31588590","order_by":2,"name":"Alison Stallings","email":"","orcid":"","institution":"The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Alison","middleName":"","lastName":"Stallings","suffix":""},{"id":337355549,"identity":"84bf62fb-5061-472d-a46e-63c38d1837d1","order_by":3,"name":"Ada Felix-Ortiz","email":"","orcid":"","institution":"The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Ada","middleName":"","lastName":"Felix-Ortiz","suffix":""},{"id":337355550,"identity":"54c15377-52d6-4e24-a241-3fa83355bbbb","order_by":4,"name":"Skanda Hebbale","email":"","orcid":"","institution":"The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Skanda","middleName":"","lastName":"Hebbale","suffix":""},{"id":337355551,"identity":"9728ec67-edb3-4211-b8b8-b8fdb640fce7","order_by":5,"name":"Luke Norton","email":"","orcid":"","institution":"The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Luke","middleName":"","lastName":"Norton","suffix":""},{"id":337355552,"identity":"10c82807-9983-40ff-a031-5737de00c588","order_by":6,"name":"Michael Mader","email":"","orcid":"https://orcid.org/0000-0002-0341-0641","institution":"South Texas Veterans Health Care System","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Mader","suffix":""},{"id":337355553,"identity":"839ad805-c390-4c89-8f56-06cd14e4290e","order_by":7,"name":"Robert Clark","email":"","orcid":"https://orcid.org/0000-0002-4892-3619","institution":"South Texas Veterans Health Care System and The University of Texas Health Science Center at San Antonio","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Clark","suffix":""}],"badges":[],"createdAt":"2024-08-06 22:50:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4870881/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4870881/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41531-025-00961-w","type":"published","date":"2025-04-24T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":81353970,"identity":"f0acaaf1-ee26-4033-a76b-b837c466df92","added_by":"auto","created_at":"2025-04-25 07:08:51","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2228841,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ClarkChanduManuscriptHFDweightlossnpjPD2024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4870881/v1_covered_edb48dc3-1e85-401e-a906-0c5c6ce26bc4.pdf"}],"financialInterests":"(Not answered)","formattedTitle":"Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson’s disease","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4870881/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4870881/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Unintentional weight loss, primarily due to the loss of fat mass rather than muscle mass, is common among patients with Parkinson’s disease (PD) and is associated with poor quality of life and accelerated disease progression. Since transgenic mice overexpressing human wild-type α-synuclein (α-Syn mice) are modestly leaner than control mice, and since diabetes, a metabolic disorder, is a major risk factor for PD, we reasoned that high-fat diet-induced diabetes/metabolic dysregulation in α-Syn mice may serve as a robust tool for exploring how early α-synuclein pathology contributes to metabolic dysregulation, leading to weight loss in PD. Thus, α-Syn and age-matched controls were fed a high-fat diet (HFD) chow (60% fat calories) ad libitum for four months. Compared with controls on HFD (control-HFD), α-Syn mice on HFD (α-Syn-HFD) were dramatically leaner. The resistance to gaining weight in α-Syn-HFD mice was accompanied by improved glucose tolerance, a dramatic decrease in fat mass, and an increase in energy expenditure. Despite this leaner phenotype and better glucose tolerance, the mortality was much higher in male α-Syn-HFD mice than in all controls, but was unaffected in females, suggesting protective effects of female sex hormones, as well as lower α-synuclein levels. Immunoblot analysis of insulin signaling in the olfactory bulb, the proposed initial seeding site of α-synuclein pathology, revealed a decrease of IGF-IRβ, p GSK, and p mTOR in α-Syn-HFD mice. Since GSK-3β and mTOR regulate synaptic plasticity, we assessed levels of PSD-95 and synaptophysin in the olfactory bulb. As anticipated, we observed a significant decrease in the levels of PSD-95, along with a potentially compensatory increase in synaptophysin levels. Our results show that α-Syn mice, when challenged with diet-induced diabetes/metabolic dysregulation, clearly reveal a profile of robust metabolic dysfunction, thus providing a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. We propose a role for olfactory dysfunction in PD-related unintentional weight loss and suggest that strategies aimed at increasing body weight/BMI will improve the quality of life and prognosis for people living with PD.","manuscriptTitle":"Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson’s disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-30 13:43:14","doi":"10.21203/rs.3.rs-4870881/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-10-14T20:41:03+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-09-02T01:48:24+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-08-24T19:37:00+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-08-22T13:22:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-08-19T08:39:53+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-08-09T01:38:53+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-08-07T18:28:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-07T15:27:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-07T07:34:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Parkinson's Disease","date":"2024-08-06T22:48:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-parkinsons-disease","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjparkd","sideBox":"Learn more about [npj Parkinson's Disease](http://www.nature.com/npjparkd/)","snPcode":"41531","submissionUrl":"https://submission.springernature.com/new-submission/41531/3","title":"npj Parkinson's Disease","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"70cea121-8f5e-49ee-aa73-154fe1145adc","owner":[],"postedDate":"August 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":35734844,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Parkinson's disease"},{"id":35734845,"name":"Biological sciences/Neuroscience/Olfactory system"}],"tags":[],"updatedAt":"2025-04-25T07:08:34+00:00","versionOfRecord":{"articleIdentity":"rs-4870881","link":"https://doi.org/10.1038/s41531-025-00961-w","journal":{"identity":"npj-parkinsons-disease","isVorOnly":false,"title":"npj Parkinson's Disease"},"publishedOn":"2025-04-24 04:00:00","publishedOnDateReadable":"April 24th, 2025"},"versionCreatedAt":"2024-08-30 13:43:14","video":"","vorDoi":"10.1038/s41531-025-00961-w","vorDoiUrl":"https://doi.org/10.1038/s41531-025-00961-w","workflowStages":[]},"version":"v1","identity":"rs-4870881","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4870881","identity":"rs-4870881","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}