Immunometabolism Biomarkers

Immunometabolism is a rising field of interest, fueled by increasing obesity rates and the effect that obesity has on the immune system and the variety of chronic conditions and diseases it may bring. Common metabolic risk factors include obesity, increased blood pressure, insulin resistance, high blood sugar levels, and abnormal blood cholesterol levels. These factors have all been found to be strong contributors to promoting metabolic abnormalities, or metabolic syndrome. Metabolic syndrome is diagnosed by the presence of at least 3 of the following: obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low-density lipoprotein. The multi-level interplay between immunological and metabolic processes is an emerging frontier, and it is now clear that the behavior of leukocytes and lymphocytes on many levels in controlled by internal metabolic properties. The complex interactions between the metabolic and immune systems offer substantial therapeutic promise for the suggested pathogenic mechanisms that may underlie many of the effects of obesity.

There are obvious medical conditions connected with metabolic syndrome. These include cardiovascular disease, type 2 diabetes, fatty liver disease, and cirrhosis. Several forms of cancer, Alzheimer’s disease, and asthma have also been proposed to link to metabolic syndrome. The connection with inflammation and the pathogenesis of each of these conditions has also been drawn. The finding that inflammation mediates many of the pathologic consequences of obesity raises the hope of exploiting current and future anti-inflammatory drugs to treat patients with obesity-associated metabolic and cardiovascular disorders. The American Heart Association estimates that 20-25% of US adults have metabolic abnormalities, and thus the dissection of the molecular underpinnings of immunological and metabolic connections has become a priority.

At AssaySolution, we offer high quality ELISA kits, customized to meet your research needs for the detection of various biomarkers such as adiponectin, insulin, and glycated hemoglobin. As biomarker research takes the spotlight, the role of immunohistochemistry within that process is increasing. Please see AssaySolution’s catalog of Premier IHC antibodies for your needs.

Listed below are a few of the biomarkers related to immunometabolism with their descriptions.

Insulin, Proinsulin, C-peptide - [Clinical Use: Diabetes mellitus, hypglycemia] Insulin is produced in the pancreas from its precursor, proinsulin. In this process, proinsulin is proteolytically cleaved into insulin (covalently linked A- and B- chains) and C-peptide. Assays for insulin, proinsulin, and C-peptide are widely used for the monitoring of hypoglycemia, and the pathogenesis and treatment of diabetes mellitus.

Adiponectin (Adn) - [Clinical Use: Type 2 diabetes] Adiponectin has been extensively studied as a prognostic and diagnostic marker for diabetes and various cardiovascular diseases. It is an abundant protein hormone that is secreted by adipocytes. Adiponectin is an insulin-sensitizing hormone with anti-diabetic, anti-inflammatory and also anti-atherogenic properties. Its main function is considered most likely to be the regulation of glucose metabolism and fatty acid oxidation. In blood, adiponectin is found in different oligomeric forms as well as in complexes with several proteins.

Glycated Hemoglobin (HbA1c) - [Clinical Use: Chronic Hyperglycemia, type 2 diabetes] Many proteins, including hemoglobin, become glycated during their life cycle. Glycated hemoglobin (HbA1c) is a form of hemoglobin that is measured to primary identify the average concentration of blood glucose during the previous 2-3 months. In diabetes mellitus, increased amounts of glycated hemoglobin have been associated with cardiovascular disease, nephropathy, neuropathy, and retinopathy. HbA1c concentration is the most widely used index of chronic hyperglycemia and routine measure-ments are important in the management of Type 2 diabetes. Glycated hemoglobin measurement is also recommended to be used to diagnose diabetes.

Retinol Binding Protein 4 (RBP4) - Retinol binding protein 4 (RBP4) transports retinol in the bloodstream and is mainly synthesized in the liver, but also secreted by adipocytes of the fat tissue. The secretion acts as a signal to surrounding cells, where there is a decrease in blood glucose concentration. RBP4 has recently been described as an adipokine and studies suggest that RBP4 levels in blood correlate with insulin-resistance and obesity. It has also been proposed that RBP4 in urine might serve as a biomarker for loss of function of the human proximal renal tubule (Norden et al., 2014). 

Fibroblast Growth Factor 21 (FGF-21) - Fibroblast growth factor 21 (FGF-21) is a hepatokine that functions to stimulate glucose uptake in adipocytes and also a key mediator of fatty acid oxidation and lipid metabolism. Humans and animals with obesity or type 2 diabetes have abnormal expression and changes of FGF-21 in the circulation. FGF-21 gene therapy is considered to be a promising therapeutic candidate for the treatment of obesity and insulin resistance. 

Lipocalin-2/NGAL - Lipocalin-2 (LCN2/NGAL), also known as neutrophil gelatinase-associated lipocalin (NGAL) is a protein involved in innate immunity by sequestrating iron to limit bacterial growth. Both intestinal and metabolic inflammation, as observed in obesity and related disorders, are associated with increased Lipocalin-2 synthesis. Increased expression of Lipocalin-2 favors inflammation via the recruitment of inflammatory cells, such as neutrophils, and the induction of proinflammatory cytokines.

Fatty Acid Binding Protein 4 (FABP4/A-FABP) - Fatty acid binding protein 4 (FABP4), also known as adipocyte FABP (A-FABP) or aP2, is mainly expressed in adipocytes and macrophages and plays a key role in the development of insulin resistance and athero-sclerosis in relation to metaflammation. FABP4 has been shown to be secreted from adipocytes in a non-classical pathway associated with lipolysis, possibly acting as an adipokine. An increased level of FABP4 is strongly associated with obesity, insulin resistance, diabetes mellitus, hypertension, and cardiovascular events.

Neutrophil Serine Proteases - Neutrophil serine proteases, including neutrophil elastase (NE), proteinase 3 (PR3) and cathepsin G (CG), are components of neutrophil azurophilic granules that play a role in the elimination of engulfed microorganisms. Degranulation and neutrophil activation can cause the release neutrophil serine proteases into circulation, where they can also serve as humoral regulators of the immune responses during inflammation. Irregular activities of neutrophil serine proteases have been associated with pathogenesis of several inflammatory and autoimmune diseases as well as diabetes.

Leptin - Leptin is a hormone that is secreted by adipocytes. It crosses the blood-brain barrier and binds to receptors in the brain. Elevated leptin levels signal the brain that the energy reservoirs are full and that there is no need for food intake. This signaling route is often impaired in obese people as a result of leptin resistance.

Ghrelin - Ghrelin is a hormone that is secreted by cells in the gastrointestinal track. Leptin and ghrelin both regulate the appetite but in contrast to leptin, ghrelin increases the appetite. Ghrelin crosses the blood-brain barrier and binds to receptors on hypothalamus.

Human Alpha 1 Antitrypsin - Alpha 1 antitrypsin (A1AT) is a protease inhibitor by covalently binding to inactivate enzymes. A1AT has been shown to prevent Type 1 diabetes development as Type 1 diabetes patients have significantly lower levels of A1AT. There is also evidence showing that the deficiency of A1AT may be associated with an increased risk in developing type 2 diabetes.

Fibroblast Growth Factor 19 (FGF-19) - FGF-19 functions as a hormone that regulates bile acid synthesis with effects on glucose and lipid metabolism. FGF-19 also has metabolic effects, affecting glucose and lipid metabolism. Patients with metabolic syndrome and insulin resistance have reduced levels of FGF-19.

C-Reactive Protein (CRP) - C-reactive protein (CRP) is an acute phase protein and has emerged as one of the most important inflammatory markers for coronary heart disease (CHD). It has been found that CRP levels are strongly associated with insulin resistance and that high sensitivity CRP (hsCRP) levels are positively correlated with BMI, waist circumference, LDL cholesterol, and blood glucose levels.

Major Urinary Protein 1 (MUP-1) - Major urinary protein 1 (MUP-1) is a lipocalin family member that is secreted into the circulation by the liver. MUP-1 binds to lipophilic pheromones and is excreted in the urine. MUP-1 has been found to regulate systemic glucose and/or lipid metabolism through the paracrine/autocrine regulation of the hepatic gluconeogenic and/or lipogenic programs, respectively. A study has shown that MUP-1 increases energy expenditure and improves glucose intolerance and insulin resistance in diabetic mice.

Plasminogen Activator Inhibitor-type-1 - Plasminogen activator inhibitor-type-1 (PAI-1) is a serine protease inhibitor, specifically inhibiting the urokinase plasminogen activator, an enzyme responsible for the cleavage of plasminogen to plasmin. Individuals with metabolic syndrome typically have elevated plasma levels of PAI-I, but the relationship between metabolic syndrome diagnostics and PAI-1 remains unclear.

[References and Suggested Readings]

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