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Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease?

Fisman EZ, Tenenbaum A - Cardiovasc Diabetol (2014)

Bottom Line: Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background.Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM.Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. zfisman@post.tau.ac.il.

ABSTRACT
Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.

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Schematic depiction of the clinical outcomes of hypoadiponectinemia. Hypoadiponectinemia leads to diminished adiponectin receptors activation accompanied by increased endothelial alterations. These factors put forth several biochemical chain reactions exerting detrimental consequences via multiple pathways. These chain reactions may act reciprocally, finally conducting to serious cardiometabolic derangement.
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Figure 1: Schematic depiction of the clinical outcomes of hypoadiponectinemia. Hypoadiponectinemia leads to diminished adiponectin receptors activation accompanied by increased endothelial alterations. These factors put forth several biochemical chain reactions exerting detrimental consequences via multiple pathways. These chain reactions may act reciprocally, finally conducting to serious cardiometabolic derangement.

Mentions: It is well established that adiponectin has an antiatherosclerotic effect via inhibition of adhesion molecules production, such as vascular cell adhesion protein 1 (VCAM-1) and selectin E [85,86]. The adiponectin-mediated suppression of nuclear factor kB, could be an important molecular mechanism for inhibiting monocytes adhesion to endothelial cells [86]. Immunohistochemistry studies show that adiponectin is not incorporated into the normal and intact vessel wall, while it presents a marked adherence to previously damaged vessel walls, like those mechanically injured by balloon catheters [87], and adiponectin may also act as a modulator for macrophage-to-foam cell transformation, slowing or inhibiting the process [88]. Moreover, experimental and clinical investigations indicate that adiponectin promotes endothelial repair and angiogenesis by increasing the number and function of endothelial progenitor cells (EPCs) [89-91]. This EPCs-mediated endothelial repair involves several stages, beginning with mobilization of EPCs from bone marrow or spleen into the bloodstream, followed by recruitment and adhesion of EPCs to the injured blood vessel wall, and finally, differentiation and tubule formation. Thus, adiponectin modulates almost every step of endothelial repair via EPCs [92,93]. A schematic representation of the multiple detrimental biological and clinical effects of hypoadiponectinemia is depicted in FigureĀ 1.


Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease?

Fisman EZ, Tenenbaum A - Cardiovasc Diabetol (2014)

Schematic depiction of the clinical outcomes of hypoadiponectinemia. Hypoadiponectinemia leads to diminished adiponectin receptors activation accompanied by increased endothelial alterations. These factors put forth several biochemical chain reactions exerting detrimental consequences via multiple pathways. These chain reactions may act reciprocally, finally conducting to serious cardiometabolic derangement.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4230016&req=5

Figure 1: Schematic depiction of the clinical outcomes of hypoadiponectinemia. Hypoadiponectinemia leads to diminished adiponectin receptors activation accompanied by increased endothelial alterations. These factors put forth several biochemical chain reactions exerting detrimental consequences via multiple pathways. These chain reactions may act reciprocally, finally conducting to serious cardiometabolic derangement.
Mentions: It is well established that adiponectin has an antiatherosclerotic effect via inhibition of adhesion molecules production, such as vascular cell adhesion protein 1 (VCAM-1) and selectin E [85,86]. The adiponectin-mediated suppression of nuclear factor kB, could be an important molecular mechanism for inhibiting monocytes adhesion to endothelial cells [86]. Immunohistochemistry studies show that adiponectin is not incorporated into the normal and intact vessel wall, while it presents a marked adherence to previously damaged vessel walls, like those mechanically injured by balloon catheters [87], and adiponectin may also act as a modulator for macrophage-to-foam cell transformation, slowing or inhibiting the process [88]. Moreover, experimental and clinical investigations indicate that adiponectin promotes endothelial repair and angiogenesis by increasing the number and function of endothelial progenitor cells (EPCs) [89-91]. This EPCs-mediated endothelial repair involves several stages, beginning with mobilization of EPCs from bone marrow or spleen into the bloodstream, followed by recruitment and adhesion of EPCs to the injured blood vessel wall, and finally, differentiation and tubule formation. Thus, adiponectin modulates almost every step of endothelial repair via EPCs [92,93]. A schematic representation of the multiple detrimental biological and clinical effects of hypoadiponectinemia is depicted in FigureĀ 1.

Bottom Line: Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background.Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM.Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors.

View Article: PubMed Central - HTML - PubMed

Affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. zfisman@post.tau.ac.il.

ABSTRACT
Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.

Show MeSH
Related in: MedlinePlus