To test the hypotheses that obesity due to a very high‐fat diet induces knee osteoarthritis (OA), and that short‐term wheel‐running exercise protects against obesity‐induced knee OA by reducing systemic inflammation and metabolic dysregulation.

Male C57BL/6J mice were fed either a control diet (13.5% kcal from fat) or a very high‐fat diet (60% kcal from fat) from age 12 weeks to age 24 weeks. From 20 to 24 weeks of age, half of the mice were housed with running wheels. The severity of knee OA was determined by assessing histopathologic features, and serum cytokines were measured using a multiplex bead immunoassay and enzyme‐linked immunosorbent assays. Body composition was quantified by dual‐energy x‐ray absorptiometry, and insulin resistance was assessed by glucose tolerance testing.

Feeding mice with a very high‐fat diet increased knee OA scores and levels of serum leptin, adiponectin, KC (mouse analog of interleukin‐8 [IL‐8]), monokine induced by interferon‐γ (CXCL9), and IL‐1 receptor antagonist to an extent in proportion to the gain in body fat (3‐fold increase in percent body fat compared to controls). Wheel‐running exercise reduced progression of OA in the medial femur of obese mice. In addition, exercise disrupted the clustering of cytokine expression and improved glucose tolerance, without reducing body fat or cytokine levels.

Obesity induced by a very high‐fat diet in mice causes OA and systemic inflammation in proportion to body fat. Increased joint loading is not sufficient to explain the increased incidence of knee OA with obesity, as wheel running is protective rather than damaging. Exercise improves glucose tolerance and disrupts the coexpression of proinflammatory cytokines, suggesting that increased aerobic exercise may act independently of weight loss in promoting joint health.