Resistin

Overview

Resistin is a cysteine-rich adipokine belonging to the resistin-like molecule (RELM) family. Identified in 2001 by Steppan and colleagues during a screen for genes upregulated in insulin-resistant mice, resistin was named for its ability to induce resistance to insulin action. The human resistin protein consists of 108 amino acids (108 aa) organized into an N-terminal signal peptide and a C-terminal cysteine-rich domain. The mature 92-amino-acid secreted protein forms homo-oligomers through intermolecular disulfide bonds.

Discovery and Species Differences

Resistin was discovered through comparative subtraction of adipocyte genes from ob/ob (leptin-deficient) and wild-type mice. Expression was dramatically increased in white adipose tissue of obese mice, correlating with impaired glucose tolerance. However, human resistin exhibits a different expression pattern, with macrophages rather than adipocytes representing the primary source, though adipocyte expression increases under inflammatory conditions.

Receptor Signaling

Resistin signals through at least two receptor systems: AdipoR1 (adiponectin receptor 1) and Toll-like receptor 4 (TLR4). Binding to AdipoR1 activates AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) pathways. Interaction with TLR4 triggers MyD88-dependent NF-kappaB activation, promoting inflammatory cytokine production. The dual receptor engagement allows resistin to integrate metabolic and inflammatory signaling.

Insulin Resistance

Resistin impairs insulin signaling through multiple mechanisms. It inhibits insulin receptor substrate-1 (IRS-1) phosphorylation and reduces Akt activation in target tissues. In liver, resistin suppresses insulin-mediated suppression of gluconeogenesis, contributing to hepatic glucose overproduction. Adipose tissue resistin promotes lipolysis, elevating circulating free fatty acids that further impair peripheral insulin sensitivity.

Inflammatory Properties

Resistin activates monocytes and macrophages, stimulating production of TNF-alpha, IL-6, IL-12, and MCP-1. It promotes macrophage polarization toward the proinflammatory M1 phenotype and enhances endothelial cell adhesion molecule expression. Circulating resistin levels correlate with C-reactive protein and predict cardiovascular events independently of traditional risk factors.

Clinical Significance

Elevated plasma resistin levels correlate with obesity, type 2 diabetes, metabolic syndrome, and cardiovascular disease. Resistin predicts incident type 2 diabetes and cardiovascular mortality in prospective cohorts. Therapeutic targeting of resistin signaling pathways represents a potential approach for mitigating inflammation-driven metabolic complications.

References

1. Steppan, C.M., et al. (2001). The hormone resistin links obesity to diabetes. Nature, 409(6818), 307-312.
2. Filkov, B., et al. (2009). Resistin and its role in metabolic diseases. Diabetes & Metabolism, 35(2), 88-94.
3. Schwartz, D.R., & Lazar, M.A. (2011). Human resistin and the relation to adipose tissue, inflammation, and disease. Clinical Chemistry, 57(1), 44-51.