Adipocyte hypertrophy and dysfunction in obesity results in ectopic fatty acid accumulation leading to lipotoxicity in tissues such as pancreas (β cells), muscle and heart, which is believed to be one of the major causes of metabolic diseases [42
]. Work from animal models suggests that PPARδ activation reduces fat burden exerting many favorable activities, including reducing weight gain, increasing skeletal muscle metabolic rate and endurance, improving insulin sensitivity and cardiovascular function and suppressing atherogenic inflammation. Therefore, the development of PPARδ agonists/modulators may be useful for treating the whole spectrum of metabolic syndrome. Nevertheless, the relevance of these findings to human pathophysiology remains to be determined. Recent epidemiology studies show evidence suggesting that PPARδ polymorphisms are associated with body mass index, fasting glucose levels and insulin resistance [44
]. The result of the first human trial with PPARδ agonist has been reported [46
]. In this study with a small cohort, healthy volunteers were given placebo or GW501516 at 2.5 mg or 10 mg once daily for 2 weeks while hospitalized and sedentary. No toxicity was observed during this treatment period. Both regimens reduced circulating TG and prevented the decline of HDL-c and apoA-I levels due to lack of physical activity. There was no information regarding weight gain. These studies, although limited, provide certain validation for results from animal work. A critical question to be addressed is whether PPARδ is oncogenic, even though the carcinogenic activity of other PPAR agonists appear to be specific to rodents. Lastly, metabolic dysregulation is now recognized as a state of low grade, chronic inflammation [23
]. Consistent with this idea, free fatty acids have been shown to induce inflammatory response through toll-like receptor 4 [47
]. Furthermore, analogous to the macrophage/endothelium interaction at the vascular wall, the crosstalk between adipocytes and adipose resident macrophages is proposed to play an important role in metabolic dysregulation and insulin resistance [48
]. Future studies designed to dissect the function of PPARδ in these processes will undoubtedly identify novel therapeutic pathways to control the progression of metabolic diseases.