Modeling metabolic disease susceptibility and resilience in genetically diverse mice

Modeling metabolic disease susceptibility and resilience in genetically diverse mice | 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 Modeling metabolic disease susceptibility and resilience in genetically diverse mice Gary Churchill, Candice Baker, Jeffrey Harder, Daniel Skelly, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6149178/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 Model organisms have provided critical insights into the basic biology of metabolic disorders, however, one of the greatest limitations to translation has been the absence of the genetic heterogeneity that is characteristic of human populations. We examined metabolic health across three genetically diverse mouse strains fed control (low fat, no sucrose) or unhealthy (high fat, high sucrose) diets and observed a wide range of metabolic responses from overt type 2 diabetes in NZO/HlLtJ mice, to obesity and glucose intolerance in C57BL/6J mice, to complete resilience in CAST/EiJ mice. Analysis of multi-tissue gene expression revealed strain- and tissue-specific responses to diet, with strongest responses in white adipose tissue and pancreatic islets. In pancreatic islets, diet response was limited to just NZO mice, which showed high levels of inflammation and associated β cell dysfunction. Adipose tissue was responsive to diet across all three strains and revealed both common and strain-specific changes in inflammatory and metabolic pathways. Using a complementary outbred mouse resource, we mapped genetic loci associated with strain-specific diet responses, including a monocyte regulatory locus on mChr19. This multi-strain approach to modeling metabolic disease revealed a prominent role of white adipose tissue and lipid-associated inflammation in the determination of individual disease risk in response to unhealthy diets. Biological sciences/Genetics Biological sciences/Systems biology Type 2 diabetes metabolic disease genetics mouse diet transcriptomics 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. 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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-6149178","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":427109460,"identity":"7d635386-bdb0-48aa-91db-cd4205dfbfd1","order_by":0,"name":"Gary Churchill","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYBAC/gYQWXMASPAwHHhQYMNMUIsESDHDMaiWBIM0wloMQARjE0QLQ4LBYcIOM2A/+0yCseFO4vb2sweBtpxn55+RwPi44hceLTzpZkAtzxLnnMlLAGq5zSxx5gCz4dk+3FoMD6SxAbUcTpwhwWMA1sJwvIFNsrEHjy3nn6FoOccsf5iBgJYbIFua4FoOMBuAbGn4gVuLxI1nzBYJxw4bz+DJAWlJZjY8c7DZsLEBtxb+/jTGGx9qDsvOYD9j/OFDhV2y3I3kgw8b/uDWAgQsEglIvGRgNDUwMLbh1cL8AZlnB6Hw2zIKRsEoGAUjCwAAkVJYBj+Uso8AAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-9190-9284","institution":"Jackson Laboratories","correspondingAuthor":true,"prefix":"","firstName":"Gary","middleName":"","lastName":"Churchill","suffix":""},{"id":427109461,"identity":"0b90845d-352c-45b7-9518-7ccba7c48875","order_by":1,"name":"Candice Baker","email":"","orcid":"https://orcid.org/0009-0008-7793-3008","institution":"The Jackson Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Candice","middleName":"","lastName":"Baker","suffix":""},{"id":427109462,"identity":"c240a69a-f744-4882-baf0-6ee431a7a138","order_by":2,"name":"Jeffrey Harder","email":"","orcid":"","institution":"The Jackson Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Jeffrey","middleName":"","lastName":"Harder","suffix":""},{"id":427109463,"identity":"809a294c-8654-4f00-8f39-a208451b071f","order_by":3,"name":"Daniel Skelly","email":"","orcid":"","institution":"The Jackson Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Skelly","suffix":""},{"id":427109464,"identity":"e126759a-0199-4c21-b15f-776525c27bad","order_by":4,"name":"Isabela Gerdes Gyuricza","email":"","orcid":"","institution":"The Jackson Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Isabela","middleName":"Gerdes","lastName":"Gyuricza","suffix":""},{"id":427109465,"identity":"72b4dbb1-7e51-4ac7-bf96-6782b4595b74","order_by":5,"name":"Margaret Gaca","email":"","orcid":"","institution":"The Jackson Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Margaret","middleName":"","lastName":"Gaca","suffix":""},{"id":427109466,"identity":"d3ec30de-fa6c-4bce-b3de-f57b2dec2107","order_by":6,"name":"Matthew Vincent","email":"","orcid":"","institution":"The Jackson Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Matthew","middleName":"","lastName":"Vincent","suffix":""},{"id":427109467,"identity":"88ed4f45-306a-4cbf-ace2-fc9069bd4d87","order_by":7,"name":"Allison Ingalls","email":"","orcid":"","institution":"The Jackson Laboratory","correspondingAuthor":false,"prefix":"","firstName":"Allison","middleName":"","lastName":"Ingalls","suffix":""},{"id":427109468,"identity":"56e3c7a4-60d4-4dcf-a7e5-b82d4b084065","order_by":8,"name":"Mark Keller","email":"","orcid":"https://orcid.org/0000-0002-7405-5552","institution":"University of Wisconsin-Madison","correspondingAuthor":false,"prefix":"","firstName":"Mark","middleName":"","lastName":"Keller","suffix":""},{"id":427109469,"identity":"5d2982b3-0073-4d16-9064-dd941ebcf230","order_by":9,"name":"Alan Attie","email":"","orcid":"https://orcid.org/0000-0002-0568-2261","institution":"University of Wisconsin - 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