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To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Male and female C57BL\/6J mice were fed Chow or HFD from 6 to 26 weeks of age (<jats:italic>n<\/jats:italic>\u2009=\u200912 per diet and sex). We performed broad metabolic phenotyping, 16\u00a0S gut microbiome analysis, targeted gene expression analysis of synovium-infrapatellar fat tissue, targeted gene expression and proteomic analysis of articular cartilage, chondrocyte metabolic profiling, and OA histopathology. Two-way ANOVA statistics were utilized to determine the contribution of sex and diet and their interaction on outcomes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Mice fed HFD weighed 1.76-fold (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and 1.60-fold (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 \u00b1 2.2%; female: 44.1 \u00b1 3.8%). HFD caused greater cartilage pathology (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.024) and synovial hyperplasia (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (<jats:italic>p<\/jats:italic>\u2009=\u20090.048), and only male mice developed osteophytes with HFD (<jats:italic>p<\/jats:italic>\u2009=\u20090.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), fatty liver (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001), and elevated serum amylase (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (<jats:italic>p<\/jats:italic>\u2009=\u20090.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of <jats:italic>Bifidobacterium<\/jats:italic> only in male mice. In knee synovium and infrapatellar fat tissue, HFD upregulated the expression of pro-inflammatory and pro-fibrotic genes predominantly in female mice. In cartilage, lipid metabolism proteins were more abundant with HFD in male mice, whereas proteins involved in glycolysis\/gluconeogenesis and biosynthesis of amino acids were greater in cartilage of female mice. Sex-dependent metabolic differences were observed in cartilage from young, healthy mice prior to pubertal maturation, but not in primary juvenile chondrocytes studied in vitro.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>HFD induced numerous sex differences in metabolic and inflammatory outcomes, especially in joint tissues, suggesting that sex-specific cellular processes are involved during development of early-stage OA with obesity.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13293-024-00680-6","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T09:15:36Z","timestamp":1733390136000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice"],"prefix":"10.1186","volume":"15","author":[{"given":"Timothy M.","family":"Griffin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika Barboza Prado","family":"Lopes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Cortassa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Batushansky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matlock A.","family":"Jeffries","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawid","family":"Makosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Jopkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmaja","family":"Mehta-D\u2019souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi K.","family":"Komaravolu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Kinter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,5]]},"reference":[{"key":"680_CR1","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.joca.2021.04.020","volume":"30","author":"KD Allen","year":"2022","unstructured":"Allen KD, Thoma LM, Golightly YM. 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