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 that in humans is encoded by the RARRES2 gene. [5] [6] [7]
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 that in humans is encoded by the RARRES2 gene. [5] [6] [7]
Retinoids 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 proteins that are members of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. RARRES1, RARRES2 (this gene), and RARRES3 are genes whose expression is upregulated by the synthetic retinoid tazarotene. RARRES2 is thought to act as a cell surface receptor. [7]
Chemerin is a chemoattractant protein that acts as a ligand for the G protein-coupled receptor CMKLR1 (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 by inflammatory and coagulation serine proteases. [8] [9]
Chemerin was found to stimulate chemotaxis of dendritic cells and macrophages to the site of inflammation. [10]
In humans, chemerin mRNA is highly expressed in white adipose tissue, liver and lung while its receptor, CMKLR1 is predominantly expressed in immune cells as well as adipose tissue. [11] Because of its role in adipocyte differentiation and glucose uptake, chemerin is classified as an adipokine.
Chemerin has been implicated in autocrine / paracrine signaling for adipocyte differentiation and also stimulation of lipolysis. [11] [12] Studies with 3T3-L1 cells have shown chemerin expression is low in pre-differentiated adipocytes [11] but its expression and secretion increases both during and after differentiation in vitro . Genetic knockdown of chemerin or its receptor, CMKLR1 impairs differentiation into adipocytes, and reduces the expression of GLUT4 and adiponectin, while increasing expression of IL-6 and insulin receptor. Furthermore, post-differentiation knockdown of chemerin reduced GLUT4, leptin, adiponectin, perilipin, and reduced lipolysis, suggesting chemerin plays a role in metabolic function of mature adipocytes. [12] Studies using mature human adipocytes, 3T3-L1 cells, and in vivo studies in mice showed chemerin stimulates the phosphorylation of the MAPKs, ERK1, and ERK2, which are involved in mediating lipolysis. [12]
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.2
Given chemerin's role as a chemoattractant and a recent finding macrophages have been implicated in chronic inflammation of adipose tissue in obesity. [13] This suggests chemerin may play an important role in the pathogenesis of obesity and insulin resistance.
Studies in mice found that feeding mice a high-fat diet, resulted in increased expression of both chemerin and CMKLR1. [6] In humans, chemerin levels are significantly different between individuals with normal glucose tolerance and individuals with type II diabetes and first degree relatives. [14] Moreover, chemerin levels show a significant correlation with body mass index, plasma triglyceride levels and blood pressure. [8]
It was found incubation of 3T3-L1 cells with recombinant human chemerin protein facilitated insulin-stimulated glucose uptake. [15] This suggests chemerin plays a role in insulin sensitivity and may be a potential therapeutic target for treating type II diabetes. [8]
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 important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.
Adipose tissue (also known as 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 endothelial cells and a variety of immune cells such as adipose tissue macrophages. Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Far from being hormonally inert, adipose tissue has, in recent years, been recognized as a major endocrine organ, as it produces hormones such as leptin, estrogen, resistin, and cytokines (especially TNFα). In obesity, adipose tissue is also implicated in the chronic release of pro-inflammatory markers known as adipokines, which are responsible for the development of metabolic syndrome, a constellation of diseases, including type 2 diabetes, cardiovascular disease and atherosclerosis. The two types of adipose tissue are white adipose tissue (WAT), which stores energy, and brown adipose tissue (BAT), which generates body heat. The formation of adipose tissue appears to be controlled in part by the adipose gene. Adipose tissue – more specifically brown adipose tissue – was first identified by the Swiss naturalist Conrad Gessner in 1551.
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 adipogenesis. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.
Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.
Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine-rich peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.
The adipokines, or adipocytokines are cytokines secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metabolic syndrome, a constellation of diseases including, but not limited to, type 2 diabetes, cardiovascular disease and atherosclerosis. The first adipokine to be discovered was leptin in 1994. Since that time, hundreds of adipokines have been discovered.
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 adipose tissues and striated muscle. The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.
Perilipin, also known as lipid droplet-associated protein, perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.
The adrenocorticotropic hormone receptor or ACTH receptor also known as the melanocortin receptor 2 or MC2 receptor is a type of melanocortin receptor (type 2) which is specific for ACTH. A G protein–coupled receptor located on the external cell plasma membrane, it is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase. The ACTH receptor plays a role in immune function and glucose metabolism.
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.
Peroxisome proliferator-activated receptor gamma, also known as the glitazone reverse insulin resistance receptor, or NR1C3 is a type II nuclear receptor functioning as a transcription factor that in humans is encoded by the PPARG gene.
Chemokine like receptor 1 also known as ChemR23 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 omega-3 fatty acid eicosapentaenoic acid-derived specialized pro-resolving molecule, resolvin E1. The murine receptor that shares almost 80% homology with the human receptor, is called Dez.
Probable G-protein coupled receptor 84 is a protein that in humans is encoded by the GPR84 gene.
3T3-L1 is a sub clonal cell line derived from the original 3T3 Swiss albino cell line of 1962. The 3T3 original cell line was isolated from a mouse embryo and propagated for 3this specific line of 3T3 cells is used to study adipose tissuerelated diseases and dysfunctions. The 3T3-L1 Swiss sub clone line has been widely utilized, since its development, due to its affinity for lipid droplet deposition in vitro. 3T3-L1 cells have a fibroblast-like morphology, but, under appropriate conditions, the cells differentiate into an adipocyte-like phenotype, providing an exemplar model for white adipocytes. 3T3-L1 cells can be utilized to study a number of cellular and molecular mechanisms related to insulin-resistance, obesity, and diabetes in vitro. Aside from its usages, this cell line is widely developed and can be purchased for continuous propagation for numerous research studies. 3T3-L1 cells of the adipocyte morphology increase the synthesis and accumulation of triglycerides and acquire the signet ring appearance of adipose cells. These cells are also sensitive to lipogenic and lipolytic hormones, as well as drugs, including epinephrine, isoproterenol, and insulin.
Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.
Adipogenesis is the formation of adipocytes from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as lipoblasts or preadipocytes which lose the potential to differentiate to other types of cells such as chondrocytes, myocytes, and osteoblasts. Terminal differentiation is that preadipocytes differentiate into mature adipocytes. Adipocytes can arise either from preadipocytes resident in adipose tissue, or from bone-marrow derived progenitor cells that migrate to adipose tissue.
Krüppel-like factor 15 is a protein that in humans is encoded by the KLF15 gene in the Krüppel-like factor family. Its former designation KKLF stands for kidney-enriched Krüppel-like factor.
Adipose tissue macrophages (ATMs) comprise tissue resident macrophages present in adipose tissue. Adipose tissue apart from adipocytes is composed of the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in extremely obese, leptin deficient mice and almost 40% in obese humans. Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity.
Asprosin is a protein hormone produced by mammals in tissues that stimulates the liver to release glucose into the blood stream. Asprosin is encoded by the gene FBN1 as part of the protein profibrillin and is released from the C-terminus of the latter by specific proteolysis. In the liver, asprosin activates rapid glucose release via a cyclic adenosine monophosphate (cAMP)-dependent pathway.
Serpin A12 is a glycoprotein that is a class A member of the serine protease inhibitor (serpin) family. In humans, Serpin A12 is encoded by the SERPINA12 gene.