Sterling Rock Falls Clinic, 101 East Miller Road, Sterling, IL, USA
* Corresponding author. Tel: +1 815 632 5093; fax: +1 815 626 5947. E-mail address: peter.toth{at}srfc.com
This editorial refers to Adiponectin, risk of coronary heart disease and correlation with cardiovascular risk markers
by D. Rothenbacher et al., on page 1640
Obesity is highly prevalent. The increased availability of food, mechanization, lifestyle alterations, and other factors have made it easier for individuals to store rather than combust energy. Epidemiologic investigation has repeatedly demonstrated that obesity increases the risk for developing atherosclerotic disease and its clinical sequelae such as myocardial infarction (MI), ischaemic cerebrovascular accident, sudden death, and peripheral vascular disease. Obesity can directly and indirectly induce a large number of metabolic changes ultimately resulting in a cluster of risk factors collectively referred to as the metabolic syndrome. The metabolic syndrome is characterized by hypertension, dyslipidaemia (increased serum levels of small, dense LDL particles and triglycerides, and reduced HDL), insulin resistance with progressive deterioration in glucose tolerance, a pro-oxidative and pro-thrombotic state, and increased systemic inflammatory tone. The metabolic syndrome significantly augments risk for developing cardiovascular disease1 and diabetes mellitus and has become epidemic in the United States, Europe, and parts of Asia.
Adipose tissue was long seen as a somewhat passive storage depot for excess oxidative substrate. A newer, more dynamic picture of adipose tissue is emerging. Adipose tissue is more appropriately characterized as an endocrine organ and is intimately involved in the regulation of appetitive behaviours and satiety, systemic inflammation, and lipid and glucose metabolism. Adipose tissue is responsive to a variety of systemic stimuli such as insulin, inflammatory mediators, and catecholamines. Visceral adipose tissue appears to be more dangerous than subcutaneous adipose tissue because it is metabolically more active. Adipocytes produce a number of signalling molecules known as adipocytokines which include leptin, tumor necrosis factor-, interleukin-6, adipsin, resistin, acylation stimulating protein, and adiponectin, among others. In recent years, adiponectin has particularly drawn the attention of investigators around the world because of its capacity to impact insulin sensitivity and glucose disposal, lipid metabolism, and risk for cardiovascular disease.
Adiponectin is exclusively produced by adipocytes and its expression is inversely related to adipose tissue mass, particularly visceral adiposity. Insulin resistance and diabetes mellitus are both associated with hypoadiponectinaemia. Insulin resistance is characterized by hyperglycaemia, secondary to a reduced capacity for insulin to inhibit hepatic gluconeogenesis and to stimulate adipose tissue and skeletal glucose uptake and oxidation. The liver, skeletal muscle, and adipose tissue have evolved a complex network of signalling pathways designed to co-ordinate the systemic availability and distribution of substrate molecules. It is currently believed that insulin resistance in skeletal muscle and the hepatic parenchyma develops as excess triglycerides accumulate in these tissues. Insulin sensitization can be re-established by reducing the severity of intramyocellular and hepatic steatosis.
Adiponectin is a 30 kDa protein that can oligomerize into a number of forms. It appears to relieve insulin resistance through a variety of mechanisms. First, adiponectin stimulates skeletal muscle glucose uptake by increasing insulin receptor tyrosine kinase activity, p38 mitogen-activated protein kinase, and the tyrosine phosphorylation of insulin receptor substrate-1.2 Secondly, adiponectin activates 5'-adenosine monophosphate protein kinase (AMPK). AMPK reduces serum hepatic gluconeogenesis by inhibiting enzymes such as phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. AMPK also promotes skeletal muscle glucose and fatty acid oxidation.3 In addition to promoting the clearance of intracellular lipid stores, increased fatty acid oxidation is beneficial on multiple other levels. High serum concentrations of fatty acids inhibit lipoprotein lipase (allowing for the accumulation of triglyceride-enriched lipoproteins in serum) and are toxic to pancreatic ß-islet cells (lipotoxicity), progressively resulting in pancreatic insufficiency and diabetes. The intravenous administration of adiponectin to obese or diabetic mice restores insulin sensitivity.4
Adiponectin is emerging as an important mediator of risk for cardiovascular disease. In a nested casecontrol study of men enroled in the Health Professionals Follow-up Study, controls had significantly higher levels of adiponectin than cases (mean serum levels of 17.9 vs. 15.6 mg/L).5 The relative risk for MI was 0.39 when comparing subjects in the highest with the lowest quintile of serum adiponectin levels. After controlling for serum levels of LDL and HDL, the relative risk was attenuated to 0.56, but it remained significant (P=0.02). Other risk factors such as family history, hypertension, and C-reactive protein did not significantly impact the relationship between adiponectin and risk for MI. In a casecontrol study of Japanese men, hypoadiponectinaemia was associated with a two-fold increased risk for developing coronary artery disease (CAD).6 These findings are plausible mechanistically as adiponectin has been shown to mediate a number of anti-atherogenic effects, including the inhibition of smooth muscle cell proliferation and macrophage foam cell formation, increased expression of matrix metalloproteinase inhibitors, and the down-regulation of adhesion molecule expression by inhibiting endothelial nuclear factor-B, among others. In a recent prospective trial of obese women, the weight loss achieved after instituting increased physical activity and a low-energy Mediterranean diet was associated with increased adiponectin, improved insulin resistance, reduced serum levels of free fatty acids and interleukins (Il-6, IL-18, and C-reactive protein), and increased HDL.7
Rothenbacher et al.8 lend important information to the relationship between adiponectin and cardiovascular disease. In this casecontrol study of German patients, these authors confirm that adiponectin levels are significantly lower in both men and women with CAD when compared with age- and gender-matched controls. When comparing subjects in the highest with the lowest quintiles for serum adiponectin, the relative risk for CAD was 0.52 after controlling for covariates, an estimate essentially identical to that found by Pischon et al.5 The authors also demonstrate a doseresponse relationship between adiponectin levels and reduced risk for CAD. Not surprisingly, adiponectin levels were negatively associated with markers of endothelial dysfunction (plasminogen activator inhibitor-1) and systemic inflammation (TNF-, C-reactive protein, and white blood cell count). When the analysis was controlled for HDL, the relationship between adiponectin and CAD was no longer significant. Controlling for the constituent apoproteins of HDL (apo A-I and A-II) also attenuated this relationship, whereas the inclusion of other apoproteins (apo CII, CIII, E, and B100) had little effect. The data suggest that a significant proportion of the increased risk for CAD associated with low serum adiponectin is attributable to associated reductions in HDL.
Adiponectin exerts multiple beneficial effects on tissue and vascular physiology. Overall benefit on cardiovascular risk reduction would represent the sum total of these effects. The data by Rothenbacher et al.8 suggest that the reductions in HDL wrought by low adiponectin levels certainly play an important role. Is this plausible? On the basis of epidemiological and clinical investigation performed over the course of the last 50 years, a majority of practicing cardiologists would likely answer in the affirmative.
In the majority of patients, irrespective of race or gender, high serum levels of HDL are atheroprotective. HDL exerts a variety of beneficial functions through its complex apoprotein, enzymatic, and phospholipid molecular machinery.9 Among the most important is this lipoprotein's ability to drive reverse cholesterol transport, the series of reactions by which HDL binds to such cells as lipid-enriched macrophages, promotes the externalization of cholesterol, and transports the excess cholesterol back to the liver for disposal. The capacity of HDL to induce atheromatous plaque regression has been confirmed experimentally in both animal and human models. HDLs are also able to increase endothelial nitric oxide production and vasodilatation, inhibit endothelial cell apoptosis, reduce thrombotic tendency by inhibiting the production of thromboxane A2 and potentiate the activities of proteins C and S, reduce LDL oxidation, and decrease the expression of endothelial cell adhesion molecules by inhibiting sphingosine kinase, among other functions. Given these findings, it is not surprising that the majority of patients with CAD have low HDL. Intensive investigation is now being focused on the development of new drugs that promote efficient HDL biosynthesis and HDL analogues that can be administered systemically. There is much hope among clinicians that these agents may be able to induce biochemical revascularization among patients with CAD.
Low HDL is a defining metabolic feature of patients with insulin resistance and metabolic syndrome and is highly prevalent among diabetics. Insulin resistance is associated with reduced lipoprotein lipase activity, the enzyme responsible for hydrolyzing the triglycerides in VLDLs and chylomicrons. Low lipoprotein lipase activity leads to increased serum triglycerides and the accumulation of lipoprotein remnant particles which are highly atherogenic.10 Under these circumstances, HDL levels can drop substantially. As the lipolysis of large lipoproteins becomes progressively more impaired, less surface coat mass is released, which can be used to form HDL in serum. HDL particles can also become more enriched with triglycerides, which render them a more attractive target for hepatic lipase, an enzyme which catabolizes the HDL to smaller particles more apt for elimination.
So how does adiponectin favourably impact this scenario? Adiponectin likely promotes HDL formation on multiple fronts. First, as noted earlier, adiponectin promotes mitochondrial fatty acid oxidation and reductions in circulating levels of fatty acids. High serum levels of fatty acids are inhibitory to lipoprotein lipase. Reducing fatty acid concentrations would remove the biochemical brake applied to lipoprotein lipase. Secondly, adiponectin activates peroxisome proliferator-activated receptor- (PPAR-
).11 PPAR-
activation up-regulates the hepatic expression of apoproteins A-I and A-II, which in turn promotes increased hepatic HDL secretion.
Does adiponectin hold therapeutic promise? Perhaps, intravenous adiponectin administration to a variety of rodent models afflicted by insulin resistance demonstrates improved insulin sensitization. In another model, adenovirus-mediated adiponectin therapy in adiponectin-deficient mice limits adverse myocardial remodelling in response to pressure overload.12 It is possible that adiponectin will also hold therapeutic promise for patients with insulin resistance and low HDL. These and other possibilities will have to be tested in human clinical trials. Therapy with the PPAR- agonists, pioglitazone and rosiglitazone, is associated with increased expression of adiponectin and improvements in insulin sensitivity and circulating levels of HDL. Weight loss and lifestyle modification also achieve these therapeutic objectives.
Adipose tissue can be either friend or foe. Fat depots certainly lend proof to the statement that too much of a good thing is bad for you. Adiponectin levels may emerge as a sensitive, reproducible, and more widely available screening tool for more precisely identifying patients at risk for insulin resistance, diabetes mellitus, and atherosclerotic disease. The wide-ranging beneficial effects of adiponectin and their implications for cardiovascular medicine certainly warrant more prospective investigation.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
References
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