Review
Chemerin: at the crossroads of inflammation and obesity

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Chemerin is a secreted protein with a complex but well-established role in immune function. Parallel lines of investigation also support the notion that chemerin is a novel adipokine that regulates adipocyte development and metabolic function as well as glucose metabolism in liver and skeletal muscle tissues. A growing body of human experimental data indicates that serum chemerin levels are elevated in patients with obesity and that they exhibit a positive correlation with various aspects of the metabolic syndrome. Thus, the dual role of chemerin in inflammation and metabolism might provide a link between chronic inflammation and obesity, as well as obesity-related disorders such as type 2 diabetes and cardiovascular disease.

Section snippets

Discovery

The chemerin gene, also known as tazarotene-induced gene 2 (TIG2) or retinoic acid receptor responder 2 (RARRES2), was originally identified as a novel retinoid-responsive gene in psoriatic skin lesions [1]. The first evidence for the biological function for the chemerin protein came later, with a report identifying it as a secreted ligand of the orphan G protein-coupled receptor chemokine-like receptor (CMKLR)1 [2]. More recent studies have demonstrated that chemerin also serves as a ligand

Structure and processing

Chemerin is translated as a 163 amino acid pre-proprotein that is secreted as a 143 amino acid (18 kDa) proprotein following proteolytic cleavage of a signal peptide 2, 8 (Figure 1). This proprotein has low biological activity, and requires further extracellular C-terminal processing by plasmin, carboxypeptidases or serine proteases of the coagulation, fibrinolytic and inflammatory cascades 2, 4, 8, 9, 10. Interestingly, the extent of C-terminal cleavage depends on the location from which

Inflammation and obesity

The first recognized function of chemerin, acting through CMKLR1, was to promote chemotaxis of immature dendritic cells (DCs) and macrophages [2]. It is now known that CMKLR1 is expressed in a number of immune cells, including immature plasmacytoid DCs, myeloid DCs, macrophages and natural killer (NK) cells 4, 10, 20 and that serum chemerin levels correlate with levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6 and C reactive protein (CRP) 21, 22.

Metabolism and obesity

In addition to having an important energy storage function, white adipose tissue serves as an active endocrine organ that secretes a number of hormone-like compounds, collectively termed adipokines 42, 43, 44. Adipokines include proinflammatory cytokines and related proteins, complement and complement-related proteins, proteins of the fibrinolytic cascade, vasoactive proteins, and other biologically active peptides with hormone-like actions. Adipokines affect adiposity, adipocyte metabolism and

Glucose homeostasis

Obesity is an established risk factor for insulin resistance and T2DM, and alterations in adipokine secretion in obesity are believed to play a significant role in the development of these metabolic disorders 72, 73, 74, 75, 76, 77, 78. The elevated serum chemerin levels observed in humans and mice suggest that chemerin might also influence the dysregulation of glucose metabolism that often occurs with obesity. However, it is important to note that hyperinsulinemia, which is commonly found in

Concluding remarks

Experimental evidence supports a role for chemerin in various aspects of human physiology/pathophysiology including obesity, inflammation and insulin resistance. The majority of human data indicates that chemerin is elevated in obesity/diabetes, and that the source of elevated serum chemerin levels is adipose tissue (Figure 2). However, the precise role of chemerin in these disorders remains unclear, and several key research questions merit further investigation (Box 1). In particular, studies

Acknowledgements

Figure 1 is based upon an original figure devised and generously provided by Dr Kerry Goralski, Dalhousie University. Research in the Sinal Laboratory is funded by the Canadian Institutes of Health Research. M.E. is the recipient of a studentship award from the Nova Scotia Health Research Foundation.

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