ReviewAdiponectin and its gene variants as risk factors for insulin resistance, the metabolic syndrome and cardiovascular disease
Introduction
Obesity is reaching epidemic proportions in developed nations [1]. This major adverse impact on health is partly due to the induction of metabolic derangements which form a cluster of cardiovascular risk factors. This cluster has been termed the metabolic syndrome. An attempt to define this syndrome was first made by the World Health Organisation in 1998, of which abnormal glucose tolerance was a key factor. A clinical definition of metabolic syndrome was produced by the National Cholesterol Education Program—adult treatment program III in 2001, which includes abdominal obesity, dyslipidaemia, hypertension, insulin resistance and prothrombotic and inflammatory states [2]. The metabolic syndrome was identified as a target for cardiovascular risk reduction, as both cardiovascular disease and all-cause mortality are increased in this syndrome [3]. There is, however, currently much debate if current definitions add any cardiovascular disease risk above the individual components or other primary risk factors not included in the definition. This would include factors such as smoking and LDL cholesterol which also tend to cluster with hypertension, etc. [4], [5].
Excess body fat is stored in adipose tissue which forms over 10% of total body weight, but it is now clear that adipocytes have functions other than simple storage cells [6]. The most significant of these appears to be the secretory capacity of the adipocyte. The adipocyte secretes a number of peptides that have been labelled adipocytokines or adipokines. Adipokines identified to date seem to function as modulators of metabolism, such as leptin and resistin, or of inflammation, such as tumour necrosis factor α (TNF), interleukin 6, adipsin (also known as complement factor D), acetylation-stimulating protein, visfatin (also known as B-cell colony-enhancing factor), plasminogen-activator inhibitor type 1 as well as other complement components and interleukins [6], [7]. The most abundantly secreted adipokine is adiponectin, making up 0.01% of circulating protein with serum concentration a thousand times greater than other hormones and 106 greater than other inflammatory cytokines [8].
Section snippets
Adiponectin
Adiponectin is induced during adipocyte differentiation and is secreted only by differentiated adipocytes, with higher levels secreted from subcutaneous fat compared to visceral fat [9]. The protein consists of 244 amino acids (30 kDa) and has three distinct domains as shown in Fig. 1, namely, a signal sequence with a variable region domain, a collagen triple helix and a globular head domain which is similar in structure to TNF and the complement factor C1q [10]. Adiponectin is part of a family
Animal models
Adiponectin knockout mice have been developed, which when fed normal chow showed no difference in body weight or adiposity at 16 or 30 weeks, although subtle differences in fat metabolism could be detected including decreased clearance of free fatty acids. However, the adiponectin knockout mice developed severe insulin resistance when fed with a high sucrose/fat diet, despite no difference in weight gain compared with wild type mice fed the same diet [18]. The insulin resistance in obese and
Atheroma and inflammation
The mechanisms responsible for the atheromatous occlusion of the coronary and other arteries have yet to be fully elucidated. A detailed discussion is beyond the scope of this review and has recently been reviewed elsewhere [65]. However, inflammation and endothelial injury caused by exposure to cardiovascular risk factors, such as the features of the metabolic syndrome, appear to be important initiating events inducing endothelial injury, possibly by a mechanism inducing oxidative stress.
Variation in the adiponectin gene in humans
Adiponectin protein is the product of Adipose most abundant gene transcript 1 (APM1) gene, also known as the adiponectin encoding adipocyte C1q and collagen containing domain (ACDC), which is found on chromosome 3q27 [102]. The gene was identified through a systemic survey of active genes in adipose tissue using complimentary DNA sequencing and spans 16 kb and three exons [103]. This area of the genome has been identified by whole genome linkage studies to be a susceptibility locus for risk for
Conclusion
Adipocytes have an increasingly recognised role in the endocrine and paracrine control of metabolism and inflammation. One of the most abundant of the adipokines is adiponectin which appears to play a role in fatty acid and glucose metabolism through a change in insulin sensitivity and activation of fuel oxidation by AMPK and PPARα. Adiponectin has a plethora of anti-inflammatory and anti-atherogenic actions including inhibition of the TNF signalling cascade, essentially acting as a TNF
Acknowledgements
DRG and SEH are supported by grants from the British Heart Foundation (FS/04/012:RG2000015).
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