Adiponectin: Probe of the molecular paradigm associating diabetes and obesity

Abstract

Type 2 diabetes is an emerging health challenge all over the world as a result of urbanization, high prevalence of obesity, sedentary lifestyle and other stress related factors compounded with the genetic prevalence. The health consequences and economic burden of the obesity and related diabetes mellitus epidemic are enormous. Different signaling molecules secreted by adipocytes have been implicated in the development of obesity and associated insulin resistance in type 2 diabetes. Human adiponectin, a 244-amino acid collagen-like protein is solely secreted by adipocytes and acts as a hormone with anti-inflammatory and insulin-sensitizing properties. Adiponectin secretion, in contrast to secretion of other adipokines, is paradoxically decreased in obesity which may be attributable to inhibition of adiponectin gene transcription. There are several mechanisms through which adiponectin may decrease the risk of type 2 diabetes, including suppression of hepatic gluconeogenesis, stimulation of fatty acid oxidation in the liver, stimulation of fatty acid oxidation and glucose uptake in skeletal muscle, and stimulation of insulin secretion. To date, no systematic review has been conducted that evaluate the potential importance of adiponectin metabolism in insulin resistance. In this review attempt has been made to explore the relevance of adiponectin metabolism for the development of diabetes mellitus. This article also identifies this novel target for prospective therapeutic research aiming successful management of diabetes mellitus.

Keywords: Adiponectin; Dyslipidemia; Insulin resistance; Obesity; Type 2 diabetes mellitus.

Figure 1

Adipocyte-derived proteins with anti-diabetic actions include leptin, adiponectin, omentin and visfatin; other factors tend to raise blood glucose including resistin, Tumor necrosis factor-α and Retinol-binding protein 4. (Adapted from Mohamed-Ali et al[31] and Rosen et al[³²]). LPL: Lipoprotein lipase; HSL: Hormone-sensitive lipase; NEFA: Non-esterified fatty acids; ASP: Acylation stimulating protein; TAG: Triacylglycerol; TNF-α: Tumor necrosis factor α; RBP4: Retinol-binding protein; IL6: Interleukin 6.

Figure 2

Structure of single-chain globular domain adiponectin (sc-gAd). A: Base region of mouse gAd structure where blue arrow determines the N terminus and red arrow determines the C terminus; B: Domain organization of human adiponectin and the sc-gAd, where there are three domains A, B and C respectively. (Adapted from Min et al[30]).

Figure 3

Proposed structure of adiponectin receptors (Adapted from Kadowaki et al[36]).

Figure 4

Northern blot analysis of AdipoR1 (top panel) and AdipoR2 (bottom panel) mRNA in mouse tissues (lanes: 1, brain; 2, heart; 3, kidney; 4, liver; 5, lung; 6, skeletal muscle; 7, spleen; 8, testis)[35]. AdipoR: Adiponectin receptors.

Figure 5

Diagram depicting the metabolic profile of wild type and AdipoR2 -/- mice (Adapted from Liu et al[38]). WT: Wild type; AdipoR 2: Adiponectin receptors 2.

Figure 6

Actions of adiponectin in different cell line (Adapted from Xu et al[42]). EC: Endothelial cell; EPCs: Endothelial progenitor cells; VSMC: Vascular smooth muscles; eNOS: Endothelial nitric oxide synthase.

Figure 7

A proposed models of adiponectin metabolic pathway and associated genes. HMW: High molecular weight; LMW: Low molecular weight AdipoR1: Adiponectin receptor 1; PPARγ: Peroxisome proliferator-activated receptor gamma; Glut4: Glucose transporter type 4; APPL1: Adaptor protein, phosphotyrosine interaction, pH domain and leucine zipper containing 1; Akt: Protein kinase B; COX2: Cyclooxygenase 2; AMPK: Adenosine monophosphate-activated protein kinase; PI3K: Phosphoinositide 3-kinase; NF-kβ: Nuclear factor kappa-light-chain-enhancer of activated B cells; TNFα: Tumor necrosis factor alpha; IL: Interleukin; p38 MAPK: p38 mitogen-activated protein kinase; HSP90: Heat shock protein 90; eNOS: Endothelial nitric oxide synthase; PEPCK: Phosphoenolpyruvate carboxykinase; NO: Nitric oxide; VCAM: Vascular cell adhesion protein; ICAM: Intercellular adhesion molecule.

Figure 8

Hypothetical scheme of adiponectin signaling and the regulation of mitochondrial function in skeletal muscle (Adapted from Civitarese et al[59]). AdipoR1: Adiponectin receptor 1; PPARγ: Peroxisome proliferator-activated receptor gamma; LKB1: Liver kinase B1; AMPKK: Adenosine monophosphate-activated protein kinase kinase; AMPK: Adenosine monophosphate-activated protein kinase; ACC2: Acetyl-CoA carboxylase 2; MEF2C: Myocyte-specific enhancer factor 2C; PPARα: Peroxisome proliferator-activated receptor alpha; PGC-1: Peroxisome proliferator-activated receptor gamma coactivator 1; mtTFA: Mitochondrial transcription factor A; SOD2: Superoxide dismutase 2; ΔψM: Mitochondrial membrane potential; ROS: Reactive oxygen species.

Figure 9

Hypothetical model showing the interrelation between adiponectin, obesity and type 2 diabetes mellitus.