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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 nonpregnant 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 importance of optimizing macronutrient, particularly protein, intake to specific levels during pregnancy, ensuring a balance that maintains maternal glucose tolerance while providing sufficient nutrients to ensure healthy offspring growth and survival.<\/jats:p>","DOI":"10.1073\/pnas.2513044123","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T17:39:09Z","timestamp":1767375549000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Distinct macronutrient ratios optimize offspring survival, growth, and maternal glucose tolerance across mouse reproduction"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3037-2118","authenticated-orcid":false,"given":"Fay","family":"Morland","sequence":"first","affiliation":[{"name":"Centre for Neuroendocrinology and Department of Anatomy, University of Otago","place":["Otago, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2215-4004","authenticated-orcid":false,"given":"Melany H.","family":"Malcolm","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology and Department of Anatomy, University of Otago","place":["Otago, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology and Department of Anatomy, University of Otago","place":["Otago, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Neyt","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology and Department of Anatomy, University of Otago","place":["Otago, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5606-2559","authenticated-orcid":false,"given":"David R.","family":"Grattan","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology and Department of Anatomy, University of Otago","place":["Otago, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4996-7189","authenticated-orcid":false,"given":"Amanda E.","family":"Brandon","sequence":"additional","affiliation":[{"name":"Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0256-7687","authenticated-orcid":false,"given":"Stephen J.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9805-7280","authenticated-orcid":false,"given":"Alistair M.","family":"Senior","sequence":"additional","affiliation":[{"name":"Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha M.","family":"Solon-Biet","sequence":"additional","affiliation":[{"name":"Charles Perkins Centre and School of Life and Environmental Sciences, University of Sydney","place":["Sydney, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5140-4468","authenticated-orcid":false,"given":"Tracy L.","family":"Perry","sequence":"additional","affiliation":[{"name":"Division of Sciences, University of Otago","place":["Dunedin, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9383-3313","authenticated-orcid":false,"given":"Michael","family":"Garratt","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology and Department of Anatomy, University of Otago","place":["Otago, New Zealand"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,1,2]]},"reference":[{"key":"e_1_3_4_1_2","first-page":"CD003395","article-title":"Treatments for gestational diabetes and impaired glucose tolerance in pregnancy","volume":"3","author":"Tuffnell D. 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