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In mice, the benefits of LP diets are sex-specific, with males exhibiting a stronger response to a LP diet than females. The reason for this sexually dimorphic response is unknown, but we hypothesized that sex hormones might be responsible for this difference. Here, we tested the role of sex hormones in the response to a LP diet by feeding intact and gonadectomized mice of both sexes either a Control (21% of calorie from protein) or LP (7% of calories from protein) diet, and assessing the effects on weight, body composition, glycemic control, and energy balance over the course of three months, followed by molecular and histological analysis of tissues from each group. We confirm that males show a stronger metabolic response to an LP diet than females, but that ovariectomy sensitizes female mice to the metabolic effects of an LP diet, making them respond more similarly to males; conversely, castration does not substantially impact the response of males to an LP diet. Molecularly, we find that gonadectomy and sex are important interactors that mediate the response of mechanistic target of rapamycin (mTOR) signaling, lipid homeostasis, and thermogenesis to an LP diet. Together, this data shows that the resistance of female mice to an LP diet is mediated by ovarian hormones and suggests the possibility that older female humans might receive enhanced benefits from LP diet feeding.<\/jats:p>","DOI":"10.64898\/2026.03.31.715667","type":"posted-content","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T20:05:18Z","timestamp":1775246718000},"source":"Crossref","is-referenced-by-count":2,"title":["Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice"],"prefix":"10.64898","author":[{"given":"Bailey A.","family":"Knopf","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"},{"name":"Cell and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Grunow","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brady","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tareq","family":"Rihawi","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Sonsalla","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"},{"name":"Comparative Biomedical Sciences Graduate Program, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariah F.","family":"Calubag","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"},{"name":"Cell and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reji","family":"Babygirija","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"},{"name":"Cell and Molecular Biology Graduate Program, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"},{"name":"Endocrinology and Reproductive Physiology Graduate Program, University of Wisconsin-Madison, Madison, WI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"},{"name":"Nutrition and Metabolism Graduate Program, University of Wisconsin-Madison, Madison, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Yang","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0079-4467","authenticated-orcid":false,"given":"Dudley W.","family":"Lamming","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705 USA"},{"name":"William S. 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