Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that in humans is encoded by the ''RARRES2''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

Function

Retinoid The retinoids are a class of chemical compounds that are vitamers of vitamin A or are chemically related to it. Retinoids have found use in medicine where they regulate epithelial cell growth. Retinoids have many important functions throughout ...

s exert biologic effects such as potent growth inhibitory and cell differentiation activities and are used in the treatment of hyperproliferative dermatological diseases. These effects are mediated by specific

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of s ...

proteins that are members of the steroid and thyroid hormone receptor superfamily of transcriptional regulators.

RARRES1 Retinoic acid receptor responder protein 1 is a protein that in humans is encoded by the ''RARRES1'' gene. This gene was identified as a retinoid acid (RA) receptor-responsive gene. It encodes a type 1 membrane protein. The gene expression, expre ...

, RARRES2 (this gene), and RARRES3 are genes whose expression is upregulated by the synthetic retinoid

tazarotene Tazarotene, sold under the brand name Tazorac, among others, is a third-generation prescription topical retinoid. It is primarily used for the treatment of plaque psoriasis and acne. Tazarotene is also used as a therapeutic for photoaged and p ...

. RARRES2 is thought to act as a cell surface receptor. Chemerin is a

chemoattractant Chemotaxis (from '' chemo-'' + '' taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemi ...

that acts as a

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ele ...

for the

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

CMKLR1 Chemokine like receptor 1 also known as ChemR23 (Chemerin Receptor 23) is a protein that in humans is encoded by the ''CMKLR1'' gene. Chemokine receptor-like 1 is a G protein-coupled receptor for the chemoattractant adipokine chemerin and the om ...

(also known as ChemR23). Chemerin is a 14 kDa protein secreted in an inactive form as prochemerin and is activated through cleavage of the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein i ...

by inflammatory and coagulation

serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. S ...

s. Chemerin was found to stimulate chemotaxis of

dendritic Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to: Biology * Dendrite, a branched projection of a neuron * Dendrite (non-neuronal), branching projections of certain skin cells and immune cells Physical *Dend ...

cells and macrophages to the site of inflammation. In humans, chemerin

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

is highly expressed in white

adipose Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular ...

tissue, liver and lung while its receptor, CMKLR1 is predominantly expressed in immune cells as well as adipose tissue. Because of its role in

adipocyte Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesi ...

differentiation and glucose uptake, chemerin is classified as an

adipokine The adipokines, or adipocytokines (Greek ', fat; ', cell; and ', movement) are cytokines ( cell signaling proteins) secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metaboli ...

Role as an adipokine

Chemerin has been implicated in

autocrine Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with p ...

paracrine Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...

signaling for adipocyte differentiation and also stimulation of

lipolysis Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most importa ...

. Studies with 3T3-L1 cells have shown chemerin expression is low in pre-differentiated

s but its expression and secretion increases both during and after differentiation ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

''. Genetic knockdown of chemerin or its receptor, CMKLR1 impairs differentiation into adipocytes, and reduces the expression of

GLUT4 Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the ''SLC2A4'' gene. GLUT4 is the insulin-regulated glucose transporter found primarily in a ...

and

adiponectin Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels as well as fatty acid breakdown. In humans it is encoded by the ''ADIPOQ'' gene and it is produce ...

, while increasing expression of IL-6 and

insulin receptor The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeo ...

. Furthermore, post-differentiation knockdown of chemerin reduced GLUT4,

leptin Leptin (from Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn dimi ...

, perilipin, and reduced

, suggesting chemerin plays a role in metabolic function of mature adipocytes. Studies using mature human adipocytes, 3T3-L1 cells, and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

'' studies in mice showed chemerin stimulates the

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

of the

MAPK A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses ...

ERK1 Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the ''MAPK3'' gene. Function The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAP kinase) famil ...

, and

ERK2 Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene. Function The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extra ...

, which are involved in mediating lipolysis. Studies in mice have shown neither chemerin nor CMKLR1 are highly expressed in brown adipose tissue, indicating that chemerin plays a role in energy storage rather than

thermogenesis Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ('' Sauromatum venosum''), and the giant w ...

.²

Role in obesity and diabetes

Given chemerin's role as a chemoattractant and a recent finding macrophages have been implicated in chronic inflammation of adipose tissue in obesity. This suggests chemerin may play an important role in the pathogenesis of obesity and

insulin resistance Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood suga ...

. Studies in mice found that feeding mice a high-fat diet, resulted in increased expression of both chemerin and CMKLR1. In humans, chemerin levels are significantly different between individuals with normal

glucose tolerance Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesit ...

and individuals with

type II diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

and first degree relatives. Moreover, chemerin levels show a significant correlation with

body mass index Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and he ...

, plasma

triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and '' glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as ...

levels and blood pressure. It was found incubation of 3T3-L1 cells with recombinant human chemerin protein facilitated insulin-stimulated glucose uptake. This suggests chemerin plays a role in insulin sensitivity and may be a potential therapeutic target for treating type II diabetes.

Function

Role as an adipokine

Role in obesity and diabetes

References

Further reading