The primary goal of this Thesis is to develop a model of diet-induced obesity (DIO), using a high-fat/high-sucrose (HFS) diet to evaluate the impact of DIO on the musculoskeletal health of rats. The overarching hypothesis is that DIO can induce deleterious musculoskeletal changes in this animal model. In the first study, the role of DIO in the onset of joint damage is assessed by superimposing the diet on a model of post-traumatic osteoarthritis (PTA) progression. This study recapitulated changes in systemic and local inflammation with DIO that had been described in the clinical literature, had not been demonstrated in a preclinical model of osteoarthritis (OA). The next study linked diet-induced knee damage, without trauma, to changes in gut microbiota for the first time. The third study explored time-course changes in systemic and local inflammatory mediators in conjunction with joint damage and response to DIO. Given the changes in the systemic inflammatory environment, the next study then evaluated other synovial joints in addition to the knee joint. This study suggested that the knee and shoulder are uniquely vulnerable to damage with DIO, while the hip joint is protected. Additionally, muscle is implicated in both OA progression and the pathophysiology of metabolic syndrome, and therefore the effects of HFS DIO on muscle were measured. The fifth study evaluated DIOinduced changes in the integrity of the Vastus Lateralis (VL) quadriceps muscle. Given the severity of changes seen in the VL, short-term exposure to HFS was then explored in the VL muscle in study six, as were diet-induced changes in the gut microbiota and systemic inflammation. Because muscles have different phenotypes, related to their substrate utilization, force-producing capacity, and fatigability, we then explored another muscle, the soleus, which was previously suggested to be protected against diet-induced changes. Collectively, this Thesis demonstrates that DIO can result in structural damage across musculoskeletal tissues, while implicating several opportunities for therapeutic intervention to mitigate or prevent damage across musculoskeletal tissues. These relations and opportunities are summarized in Chapter 10, which is an integrative review on the influence of diet-induced systemic inflammation on musculoskeletal tissues.