Chemerin

Chemerin is one of the most potent chemoattractants for plasmacytoid dendritic cells (pDC) and NK cells, acting through CMKLR1. This chemotactic activity links metabolic adipose tissue inflammation to innate immune activation. In inflamed adipose tissue, chemerin recruits pDC and NK cells that then produce IFN-alpha and cytotoxic mediators, perpetuating the inflammatory cycle. Chemerin also attracts macrophages and contributes to M1 macrophage polarization.

Chemerin is highly expressed in preadipocytes and promotes their differentiation into mature adipocytes via CMKLR1/PPARgamma signaling. Paradoxically, once adipocytes are mature, chemerin can impair insulin signaling by reducing IRS-1 phosphorylation and Akt activation. This dual role, promoting adipogenesis while impairing adipocyte insulin sensitivity - may explain some paradoxical findings in studies correlating chemerin with metabolic outcomes.

Chemerin modulates hepatic glucose output by activating CMKLR1 on hepatocytes, affecting AMPK and PI3K/Akt signaling. In pancreatic beta cells, chemerin has been shown to reduce glucose-stimulated insulin secretion. In skeletal muscle, chemerin reduces GLUT4 translocation and impairs glucose uptake. These multi-tissue effects collectively worsen glucose homeostasis, explaining the association between elevated chemerin and insulin resistance.

Multiple large clinical studies confirm elevated plasma chemerin in obesity, metabolic syndrome, and type 2 diabetes after adjusting for BMI. Weight loss interventions (bariatric surgery, caloric restriction) reduce chemerin, suggesting adipose mass drives circulating levels. PCOS patients have particularly elevated chemerin, correlating with hyperandrogenemia and insulin resistance. Chemerin may be an earlier biomarker of metabolic dysfunction than traditional markers.

Plasma chemerin independently predicts major adverse cardiovascular events (MACE) in prospective studies. It promotes vascular smooth muscle proliferation, endothelial dysfunction, and atherosclerotic plaque macrophage recruitment. In heart failure, elevated chemerin correlates with disease severity and reduced exercise tolerance. The cardiovascular risk associated with chemerin appears to involve both direct vascular effects and indirect inflammatory mechanisms.

Chemerin was originally identified as TIG2, a retinoic acid-regulated gene upregulated in psoriatic skin. It is highly expressed in psoriatic plaques and recruits pDC that drive IFN-alpha-dependent inflammation. In lupus, elevated chemerin correlates with disease activity. CMKLR1 antagonism has been explored as a therapeutic approach for inflammatory skin diseases and autoimmune conditions.