Adiponectin-Dependent and -Independent Pathways in Insulin-Sensitizing and Antidiabetic Actions of Thiazolidinediones

• AMPK, AMP-activated protein kinase
• EGP, endogenous glucose production
• FFA, free fatty acid
• GIR, glucose infusion rate
• HMW, high-molecular-weight
• TNF, tumor necrosis factor
• TZD, thiazolidinedione

The metabolic syndrome has become one of the major public health challenges worldwide (1,2) and is thought to result from obesity and obesity-linked insulin resistance, the combination of which promotes diabetes, hypertension, hyperlipidemia, and cardiovascular diseases (1,2). Obesity, defined as increased adipose tissue mass, is mainly characterized by adipocyte hypertrophy, especially in adulthood (1,2). Adipose tissue serves as the site of triglyceride storage and free fatty acid (FFA)/glycerol release in response to changing energy demands (1). Adipose tissue also participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active “adipokines,” such as FFA (3), tumor necrosis factor (TNF)-α (4), resistin (5), and leptin (6). Although the association of obesity and insulin resistance has been recognized, the mechanisms by which obesity causes systemic insulin resistance largely remain unclear. One such mechanism is upregulation of insulin resistance–inducing adipokines, such as FFA, TNF-α, and resistin (Fig. 1). In contrast to such insulin resistance–causing adipokines, adiponectin, as well as leptin, is one of the adipokines that directly sensitizes the body to insulin, and its expression and serum levels are known to be upregulated by thiazolidinediones (TZDs), a group of insulin sensitizers. In this review, we describe recent progress in research into the role of adiponectin in amelioration of insulin resistance and diabetes by TZDs.