**Background:** Osteoarthritis (OA) affects approximately 528 million people globally and is among the most expensive conditions to treat, with no pharmaceutical product available to hinder or reverse its onset. Current treatments are palliative (hyaluronic acid, platelet-rich plasma, mesenchymal stem cells) or require total knee replacement surgery, which carries risks for patients with comorbidities. Obesity is a prominent risk factor for OA, and its prevalence is rising dramatically—estimated to reach one billion people globally by 2030. While mechanical joint overload has traditionally explained the obesity-OA link, the strong association between obesity and OA in non-weight-bearing joints (e.g., hand and wrist) suggests additional metabolic mechanisms involving adipose tissue-derived mediators.
**Methods:** This is a narrative review synthesizing published literature on the metabolic contributions of obesity to OA pathogenesis, with a focus on dyslipidemia, insulin resistance, and adipokines. The authors also highlight two emerging adipokines—metrnl and retinol-binding protein 4 (RBP4)—as potential therapeutic targets.
**Key Results:** (1) Dyslipidemia: For every 5-unit increase in BMI, the risk of knee OA increases by 35%. Subjects with grade II obesity (BMI >35 kg/m²) are 4.7 times more likely to develop knee OA. Weight loss of every pound (0.45 kg) results in a four-fold reduction in knee load per step. Cholesterol accumulation in chondrocytes correlates with OA severity; cholesterol efflux receptors (LXRα, LXRβ, ABCA-1) are downregulated during OA, while cholesterol hydroxylases (CH25H, CYP7B1) are upregulated, leading to increased matrix metalloproteinases (MMPs) and ADAMTS enzymes. Statins show protective effects in in-vitro and in-vivo models. High LDL, hypertriglyceridemia, and low HDL are associated with bone marrow lesions. Free fatty acids (FFA) and oxidized-LDL activate macrophages and stimulate VEGF release, promoting cartilage degradation. (2) Insulin resistance (IR): Insulin normally acts as an anabolic factor in chondrocytes, inhibiting aggrecanase activity and blocking IL-1β and TNF-α effects. In IR, insulin receptors become less responsive, leading to TNF-α upregulation in synovium. Hyperinsulinemia increases chondrocyte proliferation but prevents differentiation and reduces thyroid hormone levels. Hyperglycemia elevates ROS and advanced glycation end products (AGE), which activate NF-κB and promote inflammation. (3) Adipokines: Leptin induces chondrocyte apoptosis via JAK2/STAT3 and mTOR pathways and stimulates MMP-1, MMP-3, MMP-13, and ADAMTS enzymes. Chemerin recruits macrophages and induces CCL2 and MMP expression. Resistin binds TLR4 and CAP1 receptors, activating p38-MAPK and NF-κB. Visfatin induces IL-1β, IL-6, TNF-α, and multiple MMPs and ADAMTS enzymes. Adiponectin upregulates TIMP-2 and induces autophagy via AMPK/mTOR activation. Progranulin maintains cartilage integrity by inhibiting ADAMTS-7/12 and blocking TNF-α effects. Vaspin reduces RANKL-induced MMP-9 and inhibits IL-1β and leptin-induced catabolic mediators. Omentin-1 inhibits IL-1β-induced cartilage degradation via JAK2/STAT3 pathway inhibition. (4) Emerging adipokines: Metrnl—higher serum levels are associated with reduced OA risk; lower serum levels are found in obese OA patients and in advanced-grade OA. Synovial fluid metrnl levels are higher in OA patients, suggesting a compensatory role. Metrnl suppresses the PI3K/Akt/NF-κB pathway, upregulates collagen II, inhibits MMP-13 and ADAMTS-5, and reduces chondrocyte pyroptosis by blocking the NLRP-3/caspase-1/GSDMD cascade. RBP4—expressed by osteoarthritic chondrocytes; positively correlates with MMP-1 and MMP-3. RBP4 impairs insulin signaling via PI3K/Akt and JAK2/STAT5 activation and stimulates JNK and NF-κB after binding TLR4.
**Clinical Implications:** This review establishes OA as a metabolic disease, not merely a mechanical wear-and-tear condition. The interconnected metabolic pathways—dyslipidemia, insulin resistance, and adipokine dysregulation—offer multiple potential therapeutic targets. Mitochondrial dysfunction is a common downstream mechanism; antioxidants such as coenzyme Q10, melatonin, resveratrol, and N-acetylcysteine show promise in preclinical models. Anti-cytokine therapies (TNF inhibitors, IL-6 antibodies, JAK inhibitors) are in early phases but carry severe adverse effects. Metrnl and RBP4 represent particularly promising novel targets because they are produced locally by chondrocytes and are directly linked to OA pathogenesis. Until disease-modifying OA drugs are developed, prevention through weight management, personalized nutrition, and digital health tools (e.g., ArmOnIA, personalized metabolic avatar) remains valuable.