Patients with metabolic OA, characterized by obesity, insulin resistance, and low-grade inflammation, often display elevated extracellular HSP70 and GRP78 in plasma and synovial fluid, suggesting that therapies dampening eHSP70-TLR signaling and restoring insulin-linked iHSP70 expression may be most effective. Here, HSPA5 is linked to obesity due to melanocortin 4 receptor deficiency.