Abstract

Obesity is increasing in significance as a global health hazard by virtue of an association with metabolic syndrome, which is characterized by abdominal obesity, hyperglycemia caused by insulin resistance, glucose intolerance, atherogenic dyslipidemia, and hypertension (1). The prevalence of obesity has increased dramatically (by about 75%) since 1980; in the United States, 33% of adults are obese and 22% have metabolic syndrome (2, 3). Although many different factors can cause metabolic syndrome, derangement of lipid homeostasis attributable to a combination of excess lipid intake and lack of physical exercise plays a major role (4). It has been suggested that adipocyte dysfunction causes excessive accumulation of intraabdominal fat that, in turn, promotes ectopic fat deposition (5–7). Recently it was shown that dyslipidemia associated with metabolic syndrome is initiated principally by hepatic overproduction of plasma lipoproteins that carry triglycerides, the very low-density lipoproteins (VLDL). Such overproduction induces a series of changes in lipoproteins, eventually resulting in the atherogenic lipid abnormalities of metabolic syndrome (8). To date, the approaches to treating the syndrome using either single drugs or drug combinations (e.g. statins, fibrates, and/or angiotensin converting enzyme inhibitors) have been less than ideal, in part because of limitations in therapeutic efficacy and drug side effects (9). Thus, it is important to develop a new and effective pharmacological therapy to prevent development of atherogenic dyslipidemia in patients with metabolic syndrome. Peroxisome proliferator-activated receptors (PPAR) are lipid-activated nuclear receptors that play multiple physiological roles, including control of fatty acid metabolism in various tissues (4). An understanding of PPAR biology could pave the way toward the development of effective therapeutic drugs for treating hypertriglyceridemia and type 2 diabetes mellitus (10). Three PPAR subtypes, namely PPAR , , and / , have been described, each of which shows distinct tissue distributions and biological activities. PPAR is mainly expressed in tissues with high fatty acid oxidation such as liver, kidney, heart, skeletal muscle, and intestine. In addition, it is expressed in vascular endothelial cells, smooth muscle cells, macrophages and T lymphocytes (11–13). Experimental and clinical studies have shown that PPAR plays a crucial role in fatty acid uptake and oxidation in the liver and heart. It is also comprised in the intake of dietary long-chain fatty acid in the gut, hepatic fatty acid synthesis, and control of inflammation (8, 11, 12). PPAR is highly expressed in white and brown adipose tissue, colon, cecum, endothelial cells, vascular smooth muscle cell, and to lesser extent in immune cells like monocytes and macrophages. PPAR is mainly involved in adipocyte proliferation and differentiation, and its agonist improves glucose homeostasis and insulin sensitivity by promoting fatty acid storage and inhibiting adipokine synthesis (8, 11, 13). PPAR / is ubiquitously expressed, but its functions were unclear until recently because no selective agonist was available. However, the development of selective

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