Sexually dimorphic metabolic effects of a high fat diet on knee osteoarthritis in mice

Abstract Background Women have a higher risk of developing osteoarthritis (OA) than men, including with obesity. 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. Methods Male and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age ( n = 12 per diet and sex). We performed broad metabolic phenotyping, 16 S 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. Results Mice fed HFD weighed 1.76-fold ( p < 0.0001) and 1.60-fold ( p < 0.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 ± 2.2%; female: 44.1 ± 3.8%). HFD caused greater cartilage pathology ( p < 0.024) and synovial hyperplasia ( p < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice ( p = 0.048), and only male mice developed osteophytes with HFD ( p = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance ( p < 0.0001), fatty liver ( p < 0.0001), and elevated serum amylase ( p < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity ( p = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of Bifidobacterium 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. Conclusions 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.