Obesity is arguably the most important modifiable risk factor for onset, progression and symptoms of knee osteoarthritis (OA). For many years the association of obesity and OA has been simply attributed to the effects of overload on weight-bearing joints. There is now a growing body of evidence that obesity is a complex syndrome in which the abnormal activation of endocrine and pro-inflammatory pathways. This metabolic triggered inflammation may play an important role in the pathogenesis of OA. Activated adipose tissue produces adipokines including leptin, adiponectin, resistin and visfatin, and increases the synthesis of pro-inflammatory cytokines, such as IL-6 and tumor necrosis factor (TNF)-α. Leptin can up-regulate collagenase matrix metalloproteinase (MMP) −13 and induce inflammation, thus may play a significant role in OA. We reported that serum levels of leptin were associated with reduced knee cartilage volume and increased hip radiographic joint space narrowing. The positive association between BMI and knee cartilage volume disappeared, and positive associations between body fat and knee cartilage volume decreased in magnitude, after adjustment for leptin. Similarly, the positive association between BMI, body fat and hip joint space narrowing disappeared after adjustment for leptin. Furthermore, we reported that higher baseline IL-6 levels were associated with greater radiographic OA, and predicted greater loss of knee cartilage volume. Change in IL-6 was also associated with change in cartilage volume. Additionally, higher baseline TNF-α levels were associated with greater radiographic OA, and change in TNF-α was associated with change in cartilage volume. These preliminary results from clinical and epidemiological studies suggest metabolic and inflammatory mechanisms play roles in the pathogenesis of OA and may also mediate the effects of obesity on OA. Further studies are required to elucidate comprehensively the roles of other adipokines/cytokines in OA.