Distinct macronutrient ratios optimize offspring survival, growth and maternal glucose tolerance across mouse reproduction

Distinct macronutrient ratios optimize offspring survival, growth and maternal glucose tolerance across mouse reproduction | 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 Distinct macronutrient ratios optimize offspring survival, growth and maternal glucose tolerance across mouse reproduction Fay Morland, Michael Garratt, Melany Malcolm, Laura Wilkinson, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6517149/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pregnancy and lactation are reproductive periods that require major energy and nutrient investment by the mother. Dietary perturbations over reproduction can impair offspring development and increase the risk of metabolic disease for the mother. However, how the intake of specific macronutrients, independent of total calorie intake, influence maternal reproductive investment and metabolic health remains poorly understood. To understand the role of protein, carbohydrate and fat intake in influencing these parameters we fed mice one of ten isocaloric diets that differed systematically in their macronutrient make-up. We allowed females to breed and observed striking effects of different macronutrients on fetal development, with protein intake having strong positive effects on offspring survival, accompanied by major shifts in the morphological structure of the placenta and placental lactogen production. However, maternal glucose tolerance was strongly impaired by high protein intake during pregnancy, with reproductive females more susceptible to the effects of these macronutrients than non-pregnant animals. Strikingly, metabolic effects were reversed after lactation, with mothers developing a resilience to the chronic effects of protein and fat intake on glucose tolerance observed in virgin animals. During lactation, we also observed that offspring development was optimized by a different ratio of macronutrients compared to during pregnancy. These results highlight the role of distinct macronutrient combinations in optimizing maternal investment over different reproductive periods, and the role of protein intake in mediating a trade-off between offspring development and maternal health. Biological sciences/Physiology/Metabolism Biological sciences/Physiology/Reproductive biology Biological sciences/Physiology/Metabolism/Metabolic diseases/Diabetes/Gestational diabetes Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable1.Modelstatistics.docx Supplementary Table 1. Model stastics Cite Share Download PDF Status: Posted 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-6517149","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":447273419,"identity":"8f8addd2-c185-4c96-b1ee-6f66e6bd2487","order_by":0,"name":"Fay Morland","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYBAC9gYILQPEhg+I0sJzAEoDsbEBQwKJWswkiNPCfsaA6UbFPR7+2c3bKj7+sLPrZ2B++IFxRx1uLTw5Bsw5Z4p5JO4cK7s5IyE5eWYDm7EE4xk2nFrsGYBactsSeBhu5Jjd5klgTjY4wGDGwNjGg9sW/jcQLfJALcU8CfVALezfgFokcGuRgNpiANTCzJNw2M7gAA/IFgM8Wp4VHM45k8BjeCOtWHJG2vEEyWaeYonEtgQ8Dkve+DinIkFO7kbyxg8fbKrt+dnbN3742IY7xBgYOID+RQKJDcxAErcdIMD+AIVrj1fxKBgFo2AUjEgAAICqSxKYWhcUAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-3037-2118","institution":"University of Otago","correspondingAuthor":true,"prefix":"","firstName":"Fay","middleName":"","lastName":"Morland","suffix":""},{"id":447273420,"identity":"2bd0f805-d8b2-4fde-9073-fdd16400e7f9","order_by":1,"name":"Michael Garratt","email":"","orcid":"https://orcid.org/0000-0002-9383-3313","institution":"University of Otago","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Garratt","suffix":""},{"id":447273421,"identity":"e4e6fb77-6c9c-4c1e-9f76-d5d17f9d7a11","order_by":2,"name":"Melany Malcolm","email":"","orcid":"","institution":"University of Otago","correspondingAuthor":false,"prefix":"","firstName":"Melany","middleName":"","lastName":"Malcolm","suffix":""},{"id":447273422,"identity":"a0b4d6f7-e25d-4d90-a30a-2302d07496b8","order_by":3,"name":"Laura Wilkinson","email":"","orcid":"","institution":"University of Otago","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Wilkinson","suffix":""},{"id":447273423,"identity":"18e43cd0-88cc-4445-91fb-6058f97e09ff","order_by":4,"name":"Christine Neyt","email":"","orcid":"","institution":"University of Otago","correspondingAuthor":false,"prefix":"","firstName":"Christine","middleName":"","lastName":"Neyt","suffix":""},{"id":447273424,"identity":"8f925862-f7e0-48a2-b5d3-f4d46fceee3c","order_by":5,"name":"David Grattan","email":"","orcid":"https://orcid.org/0000-0001-5606-2559","institution":"University of Otago","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Grattan","suffix":""},{"id":447273425,"identity":"1a1575f0-08ad-4101-be40-0c0ce29d0238","order_by":6,"name":"Stephen Simpson","email":"","orcid":"https://orcid.org/0000-0003-0256-7687","institution":"The University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Simpson","suffix":""},{"id":447273426,"identity":"2e57724e-c28b-4667-b79e-939d658ffdf2","order_by":7,"name":"Alistair Senior","email":"","orcid":"https://orcid.org/0000-0001-9805-7280","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Alistair","middleName":"","lastName":"Senior","suffix":""},{"id":447273427,"identity":"56dce07a-d31e-466b-9caa-2f66da6a46b1","order_by":8,"name":"Samantha Solon-Biet","email":"","orcid":"","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Samantha","middleName":"","lastName":"Solon-Biet","suffix":""},{"id":447273428,"identity":"ff77a3d2-f6ea-4e6b-bdd9-2fb951d1e2a7","order_by":9,"name":"Tracy Perry","email":"","orcid":"","institution":"University of Otago","correspondingAuthor":false,"prefix":"","firstName":"Tracy","middleName":"","lastName":"Perry","suffix":""}],"badges":[],"createdAt":"2025-04-24 05:10:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6517149/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6517149/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82334132,"identity":"9cc62036-940c-49da-9fb0-e9b04b120ff8","added_by":"auto","created_at":"2025-05-09 07:53:43","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5963699,"visible":true,"origin":"","legend":"Article File","description":"","filename":"FinalManuscriptNatureCommsNutritionalGeometry.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6517149/v1_covered_4a07da41-915e-433a-8981-18974a543184.pdf"},{"id":81342841,"identity":"8146d080-d774-4aba-854e-f6b4821f149e","added_by":"auto","created_at":"2025-04-25 03:48:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":78024,"visible":true,"origin":"","legend":"Supplementary Table 1. 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