Adipokines As Emerging Mediators of Immune Response and Inflammation
Authors:Francisca Lago, MD; Carlos Dieguez, MD; Juan Gómez-Reino, MD; Oreste Gualillo, MD;Faculty and Disclosures
The scientific interest in the biology of white adipose tissue (WAT) has increased since the discovery of leptin in 1994. The description of the product of the gene obese (ob) demonstrated the role of adipose tissue in the physiopathology of obesity-related diseases, and helped to increase the identification of numerous other adipokines, many of a pro-inflammatory nature. It has become increasingly evident that WAT-derived adipokines can be considered as a hub between obesity-related exogenous factors, such as nutrition and lifestyle, and the molecular events that lead to metabolic syndrome, inflammatory and/or autoimmune conditions, and rheumatic diseases. In this Review, we will discuss the progress in adipokine research, focusing particular attention to the roles of leptin, adiponectin, resistin, visfatin, and other recently identified adipokines in inflammatory, autoimmune and rheumatic diseases.
The Two Faces of White Adipose Tissue. The theory that white adipose tissue (WAT) could be an active contributor to whole-body homeostasis rather than just a fat depot became tangible with the discovery of leptin in 1994. This 16 kDa protein was found to be the product of the gene obese (ob), which is mutated in the murine form of hereditary obesity. WAT has since been found to produce more than 50 cytokines and other molecules (Figure 1). These adipokinesengage, through endocrine, paracrine, autocrine or juxtacrine mechanisms of action, in a wide variety of physiological or pathological processes,including immunity and inflammation.
Leptin: The Forerunner of the Adipokine Superfamily
Leptin is a 16 kDa non-glycosylated peptide hormone encoded by the gene obese (ob), the murine homolog of the human gene LEP. It belongs to the class I cytokine superfamily. It is mainly produced by adipocytes, and circulating leptin levels are directly correlated with WAT mass. It decreases food intake and increases energy consumption by inducing anorexigenic factors(e.g. CART [cocaine and amphetamine-regulated transcript], POMC [pro-opiomelanocortin]) and suppressing orexigenic neuropeptides (e.g. NPY [neuropeptide Y], AgRP [agouti-related peptide]and orexin). Leptin levels are gender-dependent,and are higher in women than in men even when adjusted for BMI, which might be relevant to the influence of sex on the development or frequency of certain diseases, such as osteoarthritis.
Leptin: Immune System and Inflammatory Response
Db/db mice, which lack leptin receptors, are affected by thymus atrophy, and ob/ob mice, which lack leptin, are immunodeficient. These findings might explain why the murine immune system is depressed by starvation and reduced caloric intake, both of which result in low leptin levels, and why this depression is reverted by administration of exogenous leptin. Known actions of leptin on immune responses have been recently reviewed and include modulation of monocytes/macrophages, neutrophils, basophils, eosinophils, and natural killer and dendritic cells.
Adiponectin (also known as GBP28, apM1, Acrp30, or AdipoQ) is a 244-residue protein that is produced largely by WAT. Adiponectin has structural homology with collagens VIII and X and complement factor C1q, and circulates in the blood in relatively large amounts in different molecular forms.
It increases fatty acid oxidation and reduces the synthesis of glucose in the liver. Ablation of the adiponectin gene has no dramatic effect on knock-out mice on a normal diet, but when placed on a high-fat/sucrose diet they develop severe insulin resistance and exhibit lipid accumulation in muscles. Circulating adiponectin levels tend to be low in morbidly obese patients and increase with weight loss and with the use of thiazolidinediones, which enhance sensitivity to insulin.
Resistin is a dimeric protein that received its name from its apparent induction of insulin resistance in mice. It belongs to the FIZZ (found in inflammatory zones) family (also known as RELMs, i.e. resistin-like molecules). Resistin (FIZZ3) has been found in adipocytes, macrophages and other cell types.
It has been postulated that resistin mediates insulin resistance, but this role may be limited to rodents. Earlier excitement about this theory, which provides a direct connection between adiposity and insulin resistance, was rapidly extinguished by contradictory findings in both mice and humans.
Visfatin is an insulin-mimetic adipokine that was originally discovered in liver, skeletal muscle and bone marrow as a growth factor for B lymphocyte precursors (whence its alternative name, pre-B-colony enhancing factor, or PBEF). It is upregulated in models of acute lung injury and sepsis. Circulating visfatin levels are closely correlated with WAT accumulation, visfatin mRNA levels increase in the course of adipocyte differentiation, and visfatin synthesis is regulated by several factors, including glucocorticoids, TNF, IL-6 and growth hormone. Visfatin is not only produced by WAT, but also by endotoxin challenged neutrophils, in which it prevent sapoptosis through a mechanism mediated by caspases 3 and 8.
Possible Avenues for Therapeutic Action and Conclusions
• Adipokines are soluble factors produced prevalently by white adipose tissue that have emerged as modulators of inflammation and the immune response
• Although definitive conclusions are awaited, recent evidence points to involvement of adipokines in relevant degenerative diseases such as rheumatoid arthritis and osteoarthritis
• Although many functions of these molecules remain to be investigated, adipokines stand at the interface between metabolism and immunity in modulating not only inflammation, but also immune and autoimmune reactivity
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