Review
Adiponectin and atherosclerotic disease

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Abstract

Adiponectin has been identified as one of the “adipocytokines” that are derived only from adipose tissue, and are abundantly present in circulating blood. Adiponectin has protective actions in the initiation and progression of atherosclerosis through anti-inflammatory and anti-atherogenic effects. Adiponectin levels are decreased in obesity, type 2 diabetes, and patients with coronary artery disease (CAD). Adiponectin levels were negatively correlated with the CRP levels in patients with CAD. Adiponectin plays a crucial role in the association between obesity, type 2 diabetes, and insulin resistance. Mechanisms explaining the relationship between adiponectin and insulin resistance suggest that adiponectin and tumor necrosis factor (TNF)-α inhibited each other's expression and production in adipocytes. Thiazolidinediones, which are insulin-sensitizing agents, increased the production of adiponectin through directly enhancing its gene expression. The C-terminal globular domain of adiponectin may play a central role in the protective effects against atherosclerosis. Adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) are expressed ubiquitously in most organs, especially in skeletal muscle in AdipoR1, and liver in AdipoR2. With the prospect of future basic and clinical research on the molecular structure–receptor relationship, adiponectin could become a promising target for future investigations in reducing the morbidity and mortality of atherosclerotic disease.

Introduction

Obesity, which is the accumulation of excess body fat, is associated with increasing risk for many common diseases, including dyslipidemia, hypertension, type 2 diabetes, and atherosclerotic cardiovascular disease [1], [2]. In 1998, the World Health Organization (WHO) recognized the term “metabolic syndrome” for the clustering of metabolic risk factors [3]. In 2001, The National Cholesterol Education Program Adult Treatment Program (NCEP ATP III) Guidelines defined metabolic syndrome, which includes abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance, and prothrombotic and proinflammatory states, as a secondary target for cardiovascular risk reduction, after treatment of the primary target—low density lipoprotein (LDL)-cholesterol [4]. It has been well documented that cardiovascular disease and all-cause mortality are increased in patients with metabolic syndrome [5], [6].

Adipose tissue, which accounts for more than 10% of the body weight, is currently considers to be not only a reservoir for energy storage, but also an active endocrine tissue [7]. Indeed, adipose tissue produces several proactive cytokines, the so-called “adipocytokines” [8]. Adiponectin has been identified recently as one of the adipocytokines with important metabolic effects [9], [10], [11], [12]. It is derived only from adipose tissue and is abundantly present in circulating blood. Adiponectin circulates at high concentrations ranging from 2 to 30 mg/l, which is 103 higher than the concentrations of other major hormones (e.g. leptin and cortisone), and 106 higher than those of most inflammatory cytokines [e.g. tumor necrosis factor (TNF)-α and interleukin (IL)-6] (Fig. 1A) [13]. Adiponectin is a 244 amino acid protein produced by apM1 (adipose most abundant gene transcript) cDNA (Fig. 1B) [9], and is also known as GPB28 (gelatin-binding protein of 28 kDa) in humans. The mouse homolog of adiponectin has been cloned as AcrP30 (adipocyte complement-related protein of 30 kDa) and adipoQ [11], [12]. The human adiponectin gene that is encoded by apM1 mRNA, is located on chromosome 3q27, consisting of three exons and two introns [14], [15] Moreover, the cloning of complementary DNAs encoding adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2) was reported in June 2003 [16]. Adiponectin is composed of two structurally distinct domains: a collagen-like fibrous domain and a complement C1q-like globular domain (Fig. 1B) [10]. Adiponectin belongs to the soluble collagen superfamily, and has structural homology with collagen VIII, X, complement factor C1q [9], and TNF family [17]. Both C1q and TNF family play important roles in inflammation, the immune system, and atherosclerosis. Recent reports suggested that adiponectin may have anti-inflammatory and anti-atherogenic properties. Moreover, a recent study demonstrated that the C-terminal globular domain of adiponectin protects against atherosclerosis [18]. In this review, we focus on the role of adiponectin in atherosclerotic disease and discuss the potential uses of adiponectin-associated therapies in the treatment and prevention of atherosclerotic disease.

Section snippets

Atherosclerosis is an inflammatory disease

Inflammation is an important factor in the initiation and development of atherosclerosis [19]. The first change that precedes the formation of lesions of atherosclerosis is endothelial injury, which is mediated by various inflammatory stimuli, including TNF-α. Secondary, leukocytes adhere to the endothelium, and migrate into the arterial wall, where they can transform to macrophages. Subsequently, the macrophages and migrated smooth muscle cells take up modified LDL and transform into

Adiponectin and early atherosclerotic disease

Vascular endothelial dysfunction plays an important role in pathogenesis of atherosclerosis. The measurement of forearm blood flow (FBF) during reactive hyperemia is one of the sensitive methods available for evaluating endothelial function. A recent report showed that peak FBF predicts the risk of cardiovascular events in patients with coronary artery disease [31]. Another recent report showed that peak FBF was correlated with the severity of obesity, such as waist circumference and body mass

Adiponectin in obesity, type 2 diabetes, and metabolic syndrome

Insulin resistance induced by an excess of adipose tissue is one of the major risk factor for diabetes and cardiovascular disease. Recent studies have confirmed an association between adiponectin and insulin resistance (Fig. 3). In animal models, the plasma levels of adiponectin were found to be decreased, and also correlated with insulin resistance in rhesus monkeys, which spontaneously develop obesity and type 2 diabetes [50]. Moreover, insulin resistance of lipoatorophic mice was reversed by

The increment therapies of adiponectin

Hypoadiponectinemia has been demonstrated in human subjects with obesity, type 2 diabetes, and CAD. Recent studies examined whether or not plasma adiponectin levels were increased by intervention therapies including body weight reduction, exercise training, and drug administration.

Body weight reduction increased plasma adiponectin levels in both diabetic and non-diabetic subjects [36], in obese patients who received gastric partition surgery [70], [71] and in premenopausal obese women [70]. In

Conclusions

The epidemic level of overweight and sedentary lifestyle throughout the world is leading to a dramatic increase in the prevalence of metabolic syndrome. It has been established that cardiovascular and overall mortality increase in patients with metabolic syndrome, which is closely associated with obesity, and type 2 diabetes. Prevention, early identification, and adequate treatment of metabolic syndrome are required. Various in vitro, in vivo, and human studies so far have shown that adipocyte

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