ABSTRACTLeptin is a proinflammatory adipokine that contributes to obesity‐associated osteoarthritis (OA), especially in women. However, the extent to which leptin causes knee OA separate from the effect of increased body weight is not clear. We hypothesized that leptin is necessary to induce knee OA in obese female rats but not sufficient to induce knee OA in lean rats lacking systemic metabolic inflammation. The effect of obesity without leptin signaling was modeled by comparing female lean Zucker rats to pair fed obese Zucker rats, which possess mutantfaalleles of the leptin receptor gene. The effect of leptin without obesity was modeled in female F344BN F1 hybrid rats by systemically administering recombinant rat leptin versus saline for 23 weeks via osmotic pumps. Primary OA outcomes included cartilage histopathology and subchondral bone micro‐computed tomography. Secondary outcomes included targeted cartilage proteomics, serum inflammation, and synovial fluid inflammation following an acute intra‐articular challenge with interleukin‐1β (IL‐1β). Compared to lean Zucker rats, obese Zucker rats developed more severe tibial osteophytes and focal cartilage lesions in the medial tibial plateau, with modest changes in proximal tibial epiphysis trabecular bone structure. In contrast, exogenous leptin treatment, which increased plasma leptin sixfold without altering body weight, caused mild generalized cartilage fibrillation and reduced Safranin O staining compared to vehicle‐treated animals. Leptin also significantly increased subchondral and trabecular bone volume and bone mineral density in the proximal tibia. Cartilage metabolic and antioxidant enzyme protein levels were substantially elevated with leptin deficiency and minimally suppressed with leptin treatment. In contrast, leptin treatment induced greater changes in systemic and local inflammatory mediators compared to leptin receptor deficiency, including reduced serum IL‐6 and increased synovial fluid IL‐1β. In conclusion, rat models that separately elevate leptin or body weight develop distinct OA‐associated phenotypes, revealing how obesity increases OA pathology through both leptin‐dependent and independent pathways. © 2023 The Authors.JBMR Pluspublished by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.