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

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.

Fibrate therapy and flow-mediated dilation: A systematic review and meta-analysis of randomized placebo-controlled trials

“…Finally, treatment with fibrates is associated with an increase in the levels of adiponectin [22,33,36,37,50,55], an adipose-derived factor that may improve endothelial function by multiple mechanisms. It mimics the metabolic actions of insulin [56], which exerts many cardioprotective effects and may also directly increase production of NO in the vascular wall [57]. Furthermore, adiponectin is directly involved in endothelium protection through inhibition of adhesion molecules and proinflammatory cytokine production [50,58], and by stimulation of NO production from endothelium via activation of AMP-activated protein kinase [59].…”

A new fructose-free, resistant-starch type IV-enriched enteral formula improves glycaemic control and cardiovascular risk biomarkers when administered for six weeks to elderly diabetic patients

“…In addition, resistin is an adipokine that up-regulates the expression of adhesion molecules in human endothelial cells, suggesting its potential role in atherosclerosis (33), and adhesion molecules, such as sE-selectin, sICAM-1 and sVCAM-1 are critical mediators of endothelial dysfunction (25). On the other hand, adiponectin is an insulin-sensitising adipokine that is inversely proportional to adiposity and to the risk of cardiovascular disease development (27). To the best of our knowledge, this is the first intervention trial evaluating the influence of enteral administration of a DSF on diabetes-derived cardiovascular risk consequences.…”

“…These adipokines include mainly adiponectin, leptin, TNF-α, IL-6, resistin, MCP-1, PAI-1, and others, which are usually altered in patients with established type 2 diabetes (14,(25)(26)(27). In fact, the levels of plasma adipokines may help to establish the risk to develop cardiovascular comorbidities in diabetics (23).…”

Association between serum adiponectin levels and muscular fitness in Portuguese adolescents: LabMed Physical Activity Study

“…Furthermore, our results extend this evidence by including several others potential confounders, such as insulin resistance and CRP; given that, it was reported that adiponectin has an inverse relationship with markers of inflammation such as CRP 6 and insulin resistance 7 in adolescents and that CRP and insulin resistance were also negatively associated with MF in previous studies 16, . Moreover, it is known that insulin sensitivity is influenced by dietary factors and adiponectin is recognized as having insulin sensitizing properties 7,5 . Previous studies reported that daily intake of fish or omega-3 supplementation increased adiponectin levels as well as a low caloriediet.…”

“…Adiponectin concentrations have been negatively associated with insulin resistance 5 , CRP 6 and adiposity 7 , positively correlated with HDL-cholesterol 6,8 and it is considered an independent CVD risk factor 9 . It was originally assumed that adiponectin was exclusively synthesized and expressed by adipocytes 10 .…”