Adiponectin

Adiponectin was originally identified by four independent groups using different experimental approaches and is, therefore, also called ACRP30, GBP28, apM1 and AdipoQ [1- 4]. It is primarily produced by adipocytes, is approximately 28kDa in size and circulates at high levels (5-30mg/L) in the blood. Adiponectin belongs to the complement factor C1q-like superfamily of proteins and is composed of an N-terminal signal sequence (SS), a variable domain, a collagen-like (tail) domain and a C1q-like globular domain near the C-terminus [5] (see Figure 1).

Adiponectin forms low-molecular weight (LMW) homotrimers and hexamers, and high-molecular weight (HMW) multimers of 12-18 monomers [6, 7] (see Figure 2).

Based on clinical observations, the HMW multimer is thought to be the most biologically relevant form [8]. An alternative form is created when the protein’s N-terminal collagen-like domain is cleaved by leukocyte elastase and called globular domain adiponectin [9]. ACRP30headless has been shown to be inactive and can serve as a control compound [7]. While leptin is known as a central regulator of food intake, a specific role for adiponectin has not been fully elucidated yet. Currently, most investigators are focusing on the potential anti-diabetic, anti-atherogenic, anti-proliferative and anti-inflammatory activities of adiponectin [8, 10].

Enzo Life Sciences offers human and mouse adiponectin produced in mammalian cells which is more potent than adiponectin produced in bacteria.

• In serum and tissues adiponectin exists in two different forms: a low molecular weight (LMW) form (consisting of trimeric and hexameric molecules), and a high molecular weight (HMW) form (consisting of 12-18 subunits) [1, 2].
• Adiponectin expressed in mammalian cells forms the LMW and the HMW form found in native serum, while adiponectin expressed in bacterial cells only forms the LMW form [1, 3].
• Adiponectin expressed in mammalian cells is more potent than adiponectin expressed in bacterial cells due to post-translational modifications in the collagen domain (glycosylation and hydroxylation) [4, 5].
• The HMW adiponectin seems to be the active form of the protein in vivo [2, 5, 6, 7, 8].

Control of blood glucose levels depends on the efficient action of insulin, which supports the uptake of glucose from blood (mainly into the skeletal muscle) and lowers glucose release from the liver. These fundamental functions are defective in cases of obesity and insulin resistance. In contrast to other adipokines, adiponectin plasma levels are decreased in cases of obesity and insulin resistance [1, 2], thus by unknown mechanisms. Adiponectin levels have been shown to directly correlate to insulin sensitivity and to exert insulin-sensitizing effects. The molecular background of these effects probably bases on the activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)-α, causing an increase in fatty-acid oxidation, inhibition of gluconeogenesis and suppression of triglyceride accumulation in target tissues [3-6]. It has been shown that full-length adiponectin stimulates AMPK activation in the liver, whereas globular adiponectin causes the same effect in both skeletal muscle and liver tissue [4]. In a number of studies adiponectin levels in human serum are related to insulin sensitivity and are increased by the PPAR-γ agonists, thiazolidinediones, which partly explains the insulin-sensitizing effects of this new class of antidiabetic drugs [7-9].

Several studies have shown that obese patients with cardiovascular disease (CVD) have reduced adiponectin levels compared to a healthy lean population [1]. Indeed, several [2, 3] but not all [4-6] epidemiologic studies suggest that reduced plasma adiponectin levels are independent predictors of CVD. Vasoprotection by adiponectin may result from its anti-inflammatory/anti-atherogenic potential. Adiponectin has been shown to (see Figure 4) i) inhibit TNF-α induced expression of several adhesion molecules like ICAM-1, E-selectin, and VCAM-1 on endothelial cells [7, 8]; ii) suppress the formation of foam cells by inhibiting macrophage expression of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) and scavenger receptor class A-1 (SR-A), necessary for the uptake of oxidized low density lipoproteins (LDL) [9]; iii) suppress vascular smooth muscle cell proliferation and migration by binding to growth factors, preventing their normal interaction with these cells. While adiponectin levels are reduced in metabolic conditions, increased local and/or systemic levels are observed in chronic inflammatory and autoimmune diseases.