Resistin

In rodent models, resistin suppresses insulin signaling by reducing IRS-1 tyrosine phosphorylation and Akt activation in hepatocytes and skeletal muscle. It upregulates SOCS-3 (suppressor of cytokine signaling 3), which inhibits insulin receptor signaling by targeting IRS-1 for degradation. Resistin also promotes hepatic glucose output by activating FOXO1 and PEPCK, increasing gluconeogenesis independent of insulin suppression.

Human resistin binds to CAP1 (adenylate cyclase-associated protein 1) on monocytes and macrophages, activating cAMP-PKA signaling and downstream NFkB, leading to IL-6, TNF-alpha, IL-1beta, and MCP-1 production. It also activates TLR4 signaling in some contexts. This macrophage-derived resistin amplifies inflammatory responses in metabolic tissues, atherosclerotic plaques, and synovial joints, making it a driver of chronic inflammatory disease in obese and diabetic patients.

Resistin promotes endothelial dysfunction by reducing eNOS expression and increasing ICAM-1, VCAM-1, and MCP-1 in vascular endothelial cells. It stimulates vascular smooth muscle cell proliferation and migration, contributing to neointimal hyperplasia and atherosclerosis. Elevated plasma resistin independently predicts cardiovascular events in multiple prospective cohort studies, including Framingham Heart Study subanalyses.

Elevated serum resistin correlates with BMI, insulin resistance (HOMA-IR), fasting glucose, and HbA1c in multiple large studies. However, causality in humans is debated because weight loss interventions do not consistently reduce resistin. Genetic studies (Mendelian randomization) support resistin as a causal contributor to metabolic syndrome risk in populations with specific RETN gene variants.

Meta-analyses confirm elevated resistin is independently associated with coronary artery disease, acute MI, stroke, and heart failure after adjusting for traditional risk factors. In heart failure, resistin predicts mortality beyond NT-proBNP. The proposed mechanism involves both direct cardiac effects (myocardial inflammation, fibrosis) and indirect effects via systemic inflammation and endothelial dysfunction.

Resistin is markedly elevated in rheumatoid arthritis synovial fluid, inflammatory bowel disease, NAFLD/NASH, and sepsis. In IBD, resistin produced by intestinal macrophages amplifies local inflammation. In NASH, resistin promotes hepatic stellate cell activation and fibrosis. These findings suggest resistin is a conserved amplifier of macrophage-driven inflammatory states across organ systems.