Review ArticleMonocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes
Highlights
► Historic perspectives of the pioneer studies on MCP-1. ► Role of MCP-1 in obesity-related metabolic syndrome. ► Role of MCP-1 in type 2 diabetes and diabetic complications. ► Treatments on MCP-1 over-production and inhibition of MCP-1 signaling.
Section snippets
Historical perspectives of Monocyte Chemoattractant Protein-1
1989 witnessed the birth of Monocyte Chemoattractant Protein-1 (MCP-1) into the light of scientific investigation at the National Cancer Institute, Maryland, USA. This protein was initially identified from the conditioned media of human myelomonocytic cell line as the monocyte chemotactic factor (MCF) [1]. It was further named as monocyte chemotactic and activating factor (MCAF), which was found to be rapidly produced in normal human dermal fibroblasts in response to the stimuli of
Transcriptional regulation of MCP-1
Expression of MCP-1 is ubiquitous in various cell types and is upregulated by a wide variety of stimuli. The list of MCP-1-producing cell types grew rapidly after the aforementioned pioneer studies in 1989 [13], [14], [15], [16], [17], [18]. A summary of MCP-1-producing cell types and stimuli can be found in Table 3 in a review by Van Collie et al. [8]. In addition, adipocytes have been recognized as an important source of MCP-1[19], [20].
Human MCP-1 gene consists of three exons of 145, 118 and
MCP-1 and obesity
A Pubmed keyword-guided literature search showed a linear increase of the number of publications related to “MCP-1” during the period of 1989–2010, while an exponential increase of the percentages of these publications pertaining to either “obesity” or “diabetes”, implicating a rapidly growing interest in the pathological role of this chemokine under obese and diabetic conditions.
Obesity is a result of expansion in both number and size of adipocytes. The gene expression of CC chemokines and
MCP-1 and type 2 diabetes
Type 2 diabetes comprises 95% of diabetic cases and its etiology is closely related to obesity and insulin resistance. Circulating MCP-1 has been found significantly increased in patients with type 2 diabetes [80], [81], [82], [83], [84].
A common A/G polymorphism located at position -2518 in the distal regulatory region regulates MCP-1 expression [85]. In a large cohort of German Caucasians, the MCP-1 G-2518 gene variant was found significantly and negatively correlated with plasma MCP-1 levels
Diabetic complication – cardiovascular disease
Diabetes is associated with accelerated rates of atherosclerosis. MCP-1 attracts monocytes to the inflammatory sites of vascular subendothelial space, initiating migration of monocytes into the arterial wall to form excessive macrophage-derived foam cells. Large population-based studies showed significant correlation between circulating MCP-1 and other traditional risk factor for atherosclerosis, such as serum high-sensitivity C-reactive protein (hsCRP), plasma fibrinogen, and combined carotid
Diabetic nephropathy
Diabetic nephropathy is a kidney disease that develops gradually over a period of 15–20 years after the onset of diabetes, affects ∼40% of diabetic patients, and is the primary cause of dialysis [138]. The pathologic abnormalities related to this diabetic complication include mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis [139]. The significant role of MCP-1 in the development of diabetic nephropathy has been implicated by several studies using MCP-1
Diabetic retinopathy
Diabetic retinopathy is a diabetic complication that can cause blindness. The incidence of this disease is approximately 60% after 10 years with type 1 diabetes and after 20 years with type 2 diabetes [192]. Reportedly myofibroblasts and vascular endothelial cells are the major cell types expressing MCP-1 in epiretinal membranes (ERMs), caused by changes in the vitreous humor in diabetic eyes [193]. When ERM were collected from patients with proliferative diabetic retinopathy (PDR), MCP-1 mRNA
Insulitis and islet transplantation
Insulitis is an inflammatory status in pancreatic islets, signified by mononuclear cell infiltration and destruction of insulin-producing cells. It is a causative factor of insulin dependence in both type 1 and type 2 diabetes [205]. In non-obese diabetic (NOD) mice, MCP-1 mRNA expression was found to increase with age and peak at the early phases of insulitis, and therefore the production of MCP-1 by cells could contribute to the recruitment of mononuclear cells into pancreatic islets [29].
MCP-1-specific treatments
Due to the pathological significance of MCP-1, efforts have been exerted to specifically target the signaling pathway of this chemokine. Several studies have attempted to decrease MCP-1 level in the circulation or block CCR2 activity by antibody administration. Such a neutralization of MCP-1 ameliorated glomerular crescent formation and development of interstitial fibrosis in mice [211]. However, when a MCP-1 monoclonal antibody was tested in patients with rheumatoid arthritis, the treatment
Acknowledgements
This study was made possible by Grant numbers R21 AT003874 and R21 AT005139 from NCCAM and ORWH, 5G12RR003061 (RCMI/BRIDGES), U54RR022762 (RTRN Small Grant Program), and 5P20RR016467 (INBRE II) from NCRR. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the funding agencies or the NIH.
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